# US 7,608,590 B2 · HCV NS-3 serine protease inhibitors

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- Number: US 7,608,590 B2
- Document ID: US7608590B2
- Status: Granted
- Kind: B2
- Application number: 10/572,418
- Filed: 2005-01-28
- Published: 2007-07-12
- Granted: 2009-10-27
- Earliest claimed: 2004-01-30
- Assignees: Medivir AB
- Inventors: Asa Rosenquist; Fredrik Thorstensson; Per-Ola Johansson; Ingemar Kvarnstrom; Susana Ayesa; Bjorn Classon; Laszlo Rakos; Bertil Samuelsson
- Web page: https://patentgrep.com/patent/US7608590B2

## CPC

- A61K 31/47: Quinolines; Isoquinolines
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/12: Antivirals
- A61P 31/14: for RNA viruses
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07C 235/40: having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C 237/04: the carbon skeleton being acyclic and saturated
- C07C 237/10: having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms not being part of nitro or nitroso groups
- C07C 247/04: being saturated
- C07C 271/22: to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
- C07C 281/02: Compounds containing any of the groups [IMAGE cpc-sch-C07C-0972.gif], e.g. carbazates
- C07C 309/73: to carbon atoms of non-condensed six-membered aromatic rings
- C07C 311/51: Y being a hydrogen or a carbon atom
- C07D 207/16: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 215/20: Oxygen atoms
- C07D 215/233: only one oxygen atom which is attached in position 4
- C07D 245/04: condensed with carbocyclic rings or ring systems
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 405/14: containing three or more hetero rings
- C07D 409/14: containing three or more hetero rings
- C07D 413/14: containing three or more hetero rings
- C07D 417/04: directly linked by a ring-member-to-ring-member bond
- C07D 417/14: containing three or more hetero rings
- C07D 487/04: Ortho-condensed systems
- C07K 5/0205: {containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof}
- C07K 5/06034: {the side chain containing 2 to 4 carbon atoms}
- C07K 5/06052: {Val-amino acid}
- C07C 2601/02: with a three-membered ring
- C07C 2601/08: the ring being saturated
- C07C 2601/10: the ring being unsaturated
- 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
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## Abstract

Compounds of the formula where the variables are as defined in the specification inhibit the NS3 protease of flavivirus such as hepatitis C virus (HCV). The compounds comprise a novel linkage between a heterocyclic P2 unit and those portions of the inhibitor more distal to the nominal cleavage site of the native substrate, which linkage reverses the orientation of peptidic bonds on the distal side relative to those proximal to the cleavage site.

## Claims

### Claim 1

A compound of formula I′:
wherein
A is C(═O)OR1, or C(═O)NHSO2R2,wherein;
R1 is hydrogen, C1-C6alkyl, C0-C3alkylcarbocyclyl, C0-C3alkylheterocyclyl;
R2 is C1-C6alkyl, C0-C3alkylcarbocyclyl, C0-C3alkylheterocyclyl;
wherein
R2 is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, oxo, nitrile, azido, nitro, C1-C6alkyl, C0-C3alkylcarbocyclyl, C0-C3alkylheterocyclyl, NH2CO—, Y—NRaRb, Y—O—Rb, Y—C(═O)Rb, Y—(C═O)NRaRb, Y—NRaC(═O)Rb, Y—NHSOpRb, Y—S(═O)pRb, Y—S(═O)pNRaRb, Y—C(═O)ORb, Y—NRaC(═O)ORb;
Y is independently a bond or C1-C3alkyl;
Ra is independently H or C1-C3alkyl;
Rb is independently H, C1-C6alkyl, C0-C3alkylcarbocyclyl or C0-C3alkylheterocyclyl;
p is independently 1 or 2;
M is CR7R7′;
R7 taken together with R7′ forms a C3-C6cycloalkyl ring substituted with J;
q is 1 and k is 1;
W is —CH2—, —O—, —OC(═O)NH, —OC(═O), —S—, —NH—, —NRa, —NHSO2—, —NHC(═O)NH— or —NHC(═O)—, —NHC(═S)NH— or a bond;
R8 is a ring system containing 1 or 2 saturated, partially saturated or unsaturated rings each of which has 4-7 ring atoms and each of which has 0 to 4 hetero atoms independently selected from S, O and N, the ring system being optionally spaced from W by a C1-C3 alkylene group; any of which R8 groups can be optionally mono-, di-, or tri-substituted with R9, wherein
R9 is independently selected from the group consisting of halo, oxo, nitrile, azido, nitro, C1-C6alkyl, C0-C3alkylcarbocyclyl, C0-C3alkylheterocyclyl, NH2C(═O)—, Y—NRaRb, Y—O—Rb, Y—C(═O)Rb, Y—(C═O)NRaRb, Y—NRaC(═O)Rb, Y—NHSOpRb, Y—S(═O)pRb, Y—S(═O)pNRaRb, Y—C(═O)ORb, Y—NRaC(═O)ORb; wherein said carbocyclyl or heterocyclyl is optionally substituted with R10; wherein
R10 is C1-C6alkyl, C3-C7cycloalkyl, C1-C6alkoxy, amino, amido, sulfonyl, (C1-C3 alkyl)sulfonyl, NO2, OH, SH, halo, haloalkyl, carboxyl;
E is —C(═O)—, —C(═S)—, —S(═O)2−, —S(═O)—, —C(═N—Rf)—;
Rf is H, —CN, —C(═O)NRaRb; —C(═O)C1-C3alkyl;
J is a single 3 to 10-membered saturated or partially unsaturated alkylene chain that extends from the R7/R7′ cycloalkyl to G and forms a macrocycle, which chain is optionally interrupted by one to three heteroatoms independently selected from: —O—, —S— or —NR12—, and wherein 0 to 3 carbon atoms in the chain are optionally substituted with R14; wherein;
R12 is H, C1-C6alkyl, C3-C6cycloalkyl, or C(═O)R13;
R13 is C1-C6alkyl, C0-C3alkylcarbocyclyl, C0-C3alkylheterocyclyl;
R14 is independently selected from the group consisting of H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, hydroxy, halo, amino, oxo, thio and C1-C6thioalkyl;
m is 0 ; n is 0;
G is —NRy-;
Ry is J;
R16 is H; or C1-C6alkyl, C0-C3alkylcarbocyclyl, C0-C3alkylheterocyclyl, any of which can be substituted with halo, oxo, nitrile, azido, nitro, C1-C6alkyl, C0-C3alkylcarbocyclyl, C0-C3alkylheterocyclyl, NH2CO—, Y—NRaRb, Y—O—Rb, Y—C(═O)Rb, Y—(C═O)NRaRb, Y—NRaC(═O)Rb, Y—NHSOpRb, Y—S(═O)pRb, Y—S(═O)pNRaRb, Y—C(═O)ORb, Y—NRac(═O)ORb;
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

A compound according to claim 1, with the partial structure Ia′, Ib′ or Iaa′:
where e is 1 or 2.

### Claim 3 (depends on 1)

A compound according to claim 1, wherein E is —C(═O)—.

### Claim 4 (depends on 1)

A compound according to claim 1, wherein R16 is H, C1-C3 alkyl or C3-C6 cycloalkyl.

### Claim 5 (depends on 1)

A compound according to claim 1, wherein W is —OC(═O)—, —NRa—, NHS(O)2—; —NHC(═O)— or —OC(═O)NH—.

### Claim 6 (depends on 1)

A compound according to claim 1, wherein W is —S—, a bond or —O—.

### Claim 7 (depends on 5, 6)

A compound according to claim 5 or 6 wherein R8 is optionally substituted C0-C3alkylcarbocyclyl or optionally substituted C0—C3-alkylheterocyclyl.

### Claim 8 (depends on 7)

A compound according to claim 7, wherein the C0-C3 alkyl moiety is methylene or a bond.

### Claim 9

A compound of formula I′:
wherein
A is C(═O)OR1, or C(═O)NHSO2R2, wherein;
R1 is hydrogen, C1-C6alkylcarbocyclyl, C0-C3alkylheterocyclyl;
R2 is C1-C6alkyl, C0C3alkylcarbocyclyl, C0-C3alkylheterocyclyl; wherein
R2 is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, oxo, nitrile, azido, nitro, C1-C6alkyl, C0-C3alkylcarbocyclyl, C0-C3alkylheterocyclyl, NH2CO—, Y—NRaRb, Y—O—Rb,Y—C(═O)Rb, Y—(C═O)NRaRb, Y—NRaC(═O)Rb, Y—NHSOpRb, Y—S(═O)pRb, Y—S(═O)pNRaRb, Y—C(═O)ORb, Y—NRaC(═O)ORb;
Y is independently a bond or C1-C3alkyl;
Ra is independently H or C1-C3alkyk;
Rb is independently H, C1-C6alkyl, C0-C3alkylcarbocyclyl or C0-C3alkylheterocyclyl;
p is independenly 1 or 2;
M is CR7R7′;
R7 taken together with R7′ forms a C3-C6cycloalkyl ring substituted with J;
q is 1 and k is 1;
W is —O—, —OC(═O)NH, —OC(═O), —S—, —NRa, —NHSO2—, —NHC(═O)—, or a bond;
R8 is C0-C3alkylaryl, or C0-C3alkylheteroaryl, either of which is optionally mono, di, or tri substituted with R9, wherein;
R9 is C1-C6 alkyl, C1-C6alkoxy, NO2, OH, halo, trifluoromethyl, amino, amido optionally mono- or di-substituted with C1-C6alkyl, C0-C3alkylaryl, C0-C3alkylheteroaryl, carboxyl, aryl or heteroaryl being optionally substituted with R10; wherein
R10 is C1-C6alkyl, C3-C7cycloalkyl, C1-C6alkoxy, amino optionally mono- or di-substituted with C1-C6alkyl, amido, sulfonylC1-C6alkyl, NO2, OH, halo, trifluoromethyl, carboxyl, or heteroaryl;
E is —C(═O)—, —C(═S)—, —S(═O)2, —S(═O)—, C(═N—Rf)—;
Rf is H, —H, —CN, —C(═O)NRaRb; —C(═O) C1-C3alkyl;
J is a single 3 to 10-membered saturated or partially unsaturated alkylene chain that extends from the R7/R7′ cycloalkyl to G and forms a macrocycle, which chain is optionally interrupted by one to thee heteroatoms independently selected from: —O—, —S— or —NR12—, and wherein 0 to 3 carbon atoms in the chain are optionally substituted with R14; wherein;
R12 is H, C1-C6alkyl, C3-C6cycloalkyl, or C(═O)R13;
R13 is C1-C6, C0-C3alkylcarbocyclyl, C0-C3alkylheterocyclyl;
R14 is independently selected from the group consisting of H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, hydroxyl, halo, amino, oxo, thio and C1-C6thioalkyl;
m is 0; n is 0;
G is —NRy-;
Ry is J;
R16 is H; or C1-C6alkyl, C0-C3alkylcarbocyclyl, C0-C3alkylheterocyclyl, any of which can be substituted with halo, oxo, nitrile, azido, nitro, C1-C6, C0-C3alkylcarbocyclyl, C0-C3alkylheterocyclyl, NH2CO—, Y—NRaRb, Y—O—Rb, Y—C(═))Rb, Y—(C═O)NRaRb, Y—NRaC(═O)Rb, Y—NHSOpRb, Y—S(═O)pRb,Y—S(═O)pNRaRb, Y—C(═O)Orb, Y—NRac(═O)Orb;
or a pharmaceutically acceptable salt thereof.

### Claim 10 (depends on 9)

A compound according to claim 9 wherein R9 is C1-C6 alkyl, C1-C6alkoxy, amino, di-(C1-C3 alkyl)amino, C1-C3alkylamide, aryl or heteroaryl, the aryl or heteroaryl being optionally substituted with R10; wherein
R10 is C1-C6alkyl, C3-C7cycloalkyl, C1-C6alkoxy, amino, mono- or di-C1-C3 alkylamino, amido, halo, trifluoromethyl, or heteroaryl.

### Claim 11 (depends on 10)

A compound according to claim 10, wherein, R10 is C1-C6alkyl, C1-C6alkoxy, amino optionally mono- or di substituted with C1-C3 alkyl, amido, C1-C3-alkylamide, halo, or heteroaryl.

### Claim 12 (depends on 11)

A compound according to claim 11 wherein R10 is methyl, ethyl, isopropyl, tert-butyl, methoxy, chloro, amino optionally mono- or di substituted with C1-C3 alkyl, amido, or C1-C3alkyl thiazolyl.

### Claim 13 (depends on 8)

A compound according to claim 8, wherein R8 is 1-naphthylmethyl, 2-naphthylmethyl, benzyl, 1-naphthyl, 2-naphthyl, or quinolinyl any of which is unsubstituted, mono, or disubstituted with R9.

### Claim 14 (depends on 13)

A compound according to claim 13 wherein R8 is 1-naphthylmethyl, or quinolinyl any of which is unsubstituted, mono, or disubstituted with R9.

### Claim 15 (depends on 14)

A compound according to claim 14 wherein R8 is
wherein R9a is C1-C6 alkyl; C1-C6alkoxy; thioC1-C3alkyl; amino optionally substituted with C1-C6alkyl; C0-C3alkylaryl; or C0-C3alkylheteroaryl, C0-C3alkylheterocyclyl, said aryl, heteroaryl or heterocycle being optionally substituted with R10 wherein
R10 is C1-C6alkyl, C0-C3alkylC3-C7cycloalkyl, C1-C6alkoxy, amino optionally mono- or di-substituted with C1-C6alkyl, amido, C1-C3 amide; and
R9b is C1-C6 alkyl, C1-C6-alkoxy, amino, di(C1-C3alkyl)amino, (C1-C3alkyl) amide, NO2, OH, halo, trifluoromethyl, carboxyl.

### Claim 16 (depends on 15)

A compound according to claim 15, wherein R9a is aryl or heteroaryl, either of which is optionally substituted with R10.

### Claim 17 (depends on 16)

A compound according to claim 16 , wherein R9a is selected from the group consisted of:
wherein R10 is H, C1-C6alkyl, or C0-C3alkylcycloalkyl, amino optionally mono- or di-substituted with C1-C6alkyl, amido, (C1-C3alkyl)amide.

### Claim 18 (depends on 16)

A compound according to claim 16, wherein R9a is phenyl, optionally substituted with C1-C6alkyl; C1-C6alkoxy; or halo.

### Claim 19 (depends on 15)

A compound according to claim 15, wherein R8 is:
wherein R10a is H, C1-C6alkyl, or C0-C3alkylcarbocyclyl, amino optionally mono- or di-substituted with C1-C6alkyl, amido, heteroaryl or heterocyclyl; and R9b is C1-C6 alkyl, C1-C6-alkoxy, amino, di(C1-C3 alkyl)amino, amido, NO2, OH, halo, trifluoromethyl, or carboxyl.

### Claim 20 (depends on 15)

A compound according to claim 15, wherein R9b is C1-C6-alkoxy.

### Claim 21 (depends on 1)

A compound according to claim 1, wherein A is C(═O)NHSO2R2.

### Claim 22 (depends on 21)

A compound according to claim 21, wherein R2 is optionally substituted C1-C6 alkyl.

### Claim 23 (depends on 21)

A compound according to claim 21, wherein R2 is optionally substituted C3-C7cycloalkyl.

### Claim 24 (depends on 21)

A compound according to claim 21, wherein R2 is optionally substituted C0-C6alkylaryl.

### Claim 25 (depends on 1)

A compound according to claim 1, wherein A is C(═O)OR1.

### Claim 26 (depends on 25)

A compound according to claim 25, wherein R1 is H or C1-C6 alkyl.

### Claim 27 (depends on 1)

A compound according to claim 1, wherein R7 and R7′ together define a spiro-cyclopropyl.

### Claim 28 (depends on 1)

A compound according to claim 1, wherein J is a 3 to 8-membered saturated or unsaturated alkylene chain optionally containing one to two heteroatoms independently selected from: —O—, —S— or —NR12—, wherein R12 is H, C1-C6alkyl, or —C(═O)C1-C6alkyl.

### Claim 29 (depends on 28)

A compound according to claim 28, wherein J is a 4 to 7-membered saturated or unsaturated, all carbon alkylene chain.

### Claim 30 (depends on 28)

A compound according to claim 28, wherein J is saturated or mono-unsaturated.

### Claim 31 (depends on 28)

A compound according to claim 28, wherein J is dimensioned to provide a macrocycle of 14 or 15 ring atoms.

### Claim 32 (depends on 1)

A pharmaceutical composition comprising a compound as defined in claim 1, and a pharmaceutically acceptable carrier therefor.

### Claim 33 (depends on 32)

A pharmaceutical composition according to claim 32, further comprising an additional HCV antiviral, selected from nucleoside analogue polymerase inhibitors, protease inhibitors, ribavirin and interferon.

### Claim 34 (depends on 1)

A compound according to claim 1 with formula Ihe′:
or pharmaceutically acceptable salt thereof
wherein
R16 is H, or C1-C6alkyl;
J is a single 3 to 10-membered saturated or partially unsaturated alkylene chain;
q is 1 and k is 1;
A is C(═O)OR1, or C(═O)NHSO2R2, wherein
R1 is hydrogen or C1-C6alkyl;
R2 is C1-C6alkyl, C0-C3alkylcarbocyclyl, C0-C3alkylheterocyclyl;
W is —O— or —OC(═O)NH—;
R8 is C0-C3alkylaryl or C0-C3alkylheteroaryl, either of which is optionally mono, di, or tri substituted with R9, wherein;
R9 is C1-C6alkyl, C1-C6alkoxy, NO2, OH, halo, trifluoromethyl, amino or amido optionally mono- or di-substituted with C1-C6alkyl, C0-C3alkylaryl, C0-C3alkylheteroaryl, carboxyl, said aryl or heteroaryl being optionally substituted with R10;wherein
R10 is C1-C6alkyl, C3-C7cycloalkyl, C1-C6alkoxy, amino optionally mono- or di-substituted with C1-C6alkyl, C1-C3alkyl amide, sulfonylC1-C3alkyl, NO2, OH, halo, trifluoromethyl, carboxyl or heteroaryl.

### Claim 35 (depends on 34)

A compound according to claim 34, wherein J is a single 5-8 membered saturated or partially unsaturated alkylene chain.

### Claim 36 (depends on 34)

A compound according to claims 34, wherein J is monounsaturated.

### Claim 37 (depends on 36)

A compound according to claim 36, wherein J has one double bond spaced one carbon atom from the cyclopropyl group depicted in the formula Ihe′.

### Claim 38 (depends on 34)

A compound according to claim 34, wherein R8 is the group
wherein R9a is C0-C3alkylaryl, C0-C3alkylheteroaryl, or C0-C3alkylheterocyclyl; said aryl, heteroaryl or heterocyclyl being optionally substituted with R10 wherein R10 is C1-C6alkyl, amino, amino mono- or disubstituted with C1-C6alkyl or NHC(═O)C1-C6alkyl; and
R9b is C1-C6alkoxy; or
R8 is C0-C3alkylaryl wherein the aryl group is optionally substituted with 1-2 substituents selected from C0-C3alkylheterocyclyl and trifluoC1-C6alkyl; and wherein the C0-C3alkylheterocyclyl is optionally substituted with R10.

### Claim 39 (depends on 38)

A compound according to claim 38, wherein R9a is phenyl,
wherein R10 is H, C1-C6alkyl, amino, amino mono or disubstituted with C1-C3alkyl.

### Claim 40 (depends on 34)

A compound according to claim 34, wherein A is C(═O)NHS(═O)2R2.

### Claim 41 (depends on 40)

A compound according to claim 40, wherein R2 is optionally substituted cycloalkyl.

### Claim 42 (depends on 41)

The compound according to claim 41 wherein R2 is optionally substituted cyclopropyl.

### Claim 43 (depends on 4)

A compound according to claim 4, wherein R16 is methyl.

### Claim 44 (depends on 9)

A compound according to claim 9, wherein W is —O—.

### Claim 45

A compound selected from the group consisting of:
19-(7-Methoxy-2-phenyl-quinolin-4-yloxy)-2, 16-dioxo-3,15,17-triaza-tricyclo[15.3.0.0*4,6*]icos-7-ene-4,14-dicarboxylic acid 4-ethyl ester 14-methyl ester;
19-(7-Methoxy-2-phenyl-quinolin-4-yloxy)-2,16-dioxo-3,15,17-triaza-tricyclo[15.3.0.0*4,6*]icos-7-ene-3,14-dicarboxylic acid 3-ethyl ester;
14-[(Cyclohexyl-methylcarbamoyl-methyl)-19-(7-methoxy-2-phenyl-quinolin-4-yloxy)-2,16-dioxo-3, 15,17-triaza-tricyclo[15.3.0.0*4,6*]icos-7-ene-4-carboxylic acid 3-ethyl ester;
14-[(Cyclohexyl-methylcarbamoyl-methyl)-19-(7-methoxy-2-phenyl-quinolin-4-yloxy)-2,16-dioxo-3,15,17-triaza-tricyclo[15.3.0.0*4,6*]icos-7-ene-4-carboxylic acid;
[14-Cyclopropanesulfonylaminocarbonyl-17(7-methoxy-2-phenyl-quinolin-4-yloxy)-2,14-dioxo-3,13,15-triaza-tricyclo[13.3.0.0*4,6*]octadec-7-en-13-yl]-carbamic acid ter.butyl ester;
17-(7-Methoxy-2-phenyl-quinolin-4-yloxy)-2,14-dioxo-3,13,15-triaza-tricyclo[13.3.0.0.*4,6*]octadec-7-ene-4-carboxylic acid ethyl ester;
17-(7-Methoxy-2-phenyl-quinolin-4-yloxy)-2,14-dioxo-3,13,15-triaza-tricyclo[13.30.0.*4,6*]octadec-7-ene-4-carboxylic acid; or a pharmaceutically acceptable salt thereof.

### Claim 46 (depends on 45)

A pharmaceutical composition comprising a compound as defined in claim 45, and a pharmaceutically acceptable carrier therefor.

### Claim 47 (depends on 10)

A pharmaceutical composition comprising a compound as defined in claim 10, and a pharmaceutically acceptable carrier therefor.