Pyrrolopyrimidine derivatives useful as inhibitors of influenza virus replication

1. A compound having a structure of one of the following formulae:

wherein

a dashed line represents either a single or a double bond, L is:

i) H,

ii) —C 1-6 alkyl, —C 1-6 alkyl-OCONR 2 , —C 1-6 alkyl-CONR 2 , C 1-6 alkyl-CO 2 R, C 1-6 alkyl-COR, C 1-6 alkyl-NRC(O)NR 2 , C 1-6 alkyl-NRC(O)OR, C 1-6 alkyl-NRC(O)R, and C 1-6 alkyl-NR 2 , wherein the C 2-6 alkyl can optionally include a double bond;

iii) C 5-6 cycloalkyl-OCONR 2 , C 5-6 cycloalkyl-CONR 2 , C 5-6 cycloalkyl-CO 2 R, C 5-6 cycloalkyl-COR, C 5-6 cycloalkyl-NRC(O)NR 2 , C 5-6 cycloalkyl-NRC(O)OR, C 5-6 cycloalkyl-NRC(O)R, and C 5-6 cycloalkyl-NR 2 , where the cycloalkyl ring can be substituted with from one to three C 1-6 alkyl groups, and where the C 5-6 cycloalkyl ring can optionally include a double bond, an oxygen, or an NR group;

iv) —C 1-6 alkyl-O 5-6 cycloalkyl, —C 1-6 alkyl—C 5-6 cycloalkyl-OCONR 2 , —C 1-6 alkyl—C 5-6 cycloalkyl—CONR 2 , —C 1-6 alkyl—C 5-6 cycloalkyl—CO 2 R, —C 1-6 alkyl—C 5-6 cycloalkyl—COR, —C 1-6 alkyl—C 5-6 cycloalkyl—NRC(O)NR 2 , —C 1-6 alkyl—C 5-6 cycloalkyl—NRC(O)OR, —C 1-6 alkyl—C 5-6 cycloalkyl—NRC(O)R, and —C 1-6 alkyl—C 5-6 cycloalkyl—NR 2 , where the cycloalkyl ring can be substituted with from one to three C 1-6 alkyl groups, and where the C 5-6 cycloalkyl ring can optionally include a double bond, an oxygen, or an NR group;

v) 2.2.2 bicyclooctyl-OCONR 2 , 2.2.2 bicyclooctyl-CONR 2 , 2.2.2 bicyclooctyl-CO 2 R, 2.2.2 bicyclooctyl-COR, 2.2.2 bicyclooctyl-NRC(O)NR 2 , 2.2.2 bicyclooctyl-NRC(O)OR, 2.2.2 bicyclooctyl-NRC(O)R, and 2.2.2 bicyclooctyl-NR 2 , wherein the 2.2.2 bicyclooctyl ring can optionally include a double bond;

R is H, C 1-6 alkyl, C 1-6 alkyl-CO 2 R 1 , —CO 2 R 1 , CON(R 1 ) 2 , or C 1-6 alkyl-CON(R 1 ) 2 , and R 1 is H or C 1-6 alkyl;

each R 2 is independently H, halo, —CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CO 2 R, CONR 2 , phenyl, pyridinyl, thiophenyl, furanyl, or imidazolyl, wherein the phenyl, pyridinyl, thiophenyl, furanyl, or imidazolyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, C 1-6 alkoxy, C 2-8 alkoxyalkyl, alkoxycarbonyl, C 1-8 alkyl, arylalkoxycarbonyl, C 2-6 alkenyl, C 2-6 alkynyl, carboxy, halogen, haloalkyl, N 3 , CN, N(R′) 2 , SR′, OCOR′, N(COR′)R′, N(COR′)COR′, SCOR′, S(O) 2 NR′ 2 , S(O) 2 R′, and each R′ is independently H or C 1-6 alkyl;

R 3 is H, or —SO 2 -phenyl, wherein the phenyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, C 1-6 alkoxy, C 2-8 alkoxyalkyl, alkoxycarbonyl, C 1-8 alkyl, arylalkoxycarbonyl, C 2-6 alkenyl, C 2-6 alkynyl, carboxy, halogen, haloalkyl, N 3 , CN, N(R′) 2 , SR′, OCOR′, N(COR′)R′, N(COR′)COR′, SCOR′, S(O) 2 NR′ 2 , S(O) 2 R′, and each R′ is independently H or C 1-6 alkyl;

wherein a C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl moiety, wherever it occurs, can optionally be substituted with from one to three substituents which are not further substituted and which are independently selected from the group consisting of —CN, thio, aryl—C 1-6 alkyl, pyridinyl, ethoxymethyl-pyridinyl, indolinyl, C 1-6 alkyl, C 1-6 alkyl—C 3-6 cycloalkyl, C 3-6 cycloalkyl, —C 1-6 thioalkyl, C 1-6 haloalkyl, —C 1-6 hydroxyalkyl, —C 1-6 alkoxy, —C 1-6 alkoxy—C 1-6 alkoxy, —C 1-6 alkoxy—C 1-6 alkoxy—C 1-6 alkoxy, CO 2 H, CO 2 C 1-6 alkyl, CONH 2 , CONHC 1-6 alkyl, and —CON(C 1-6 alkyl) 2 ; and

wherein if two alkyl groups reside on an amide moiety, they can optionally together form a 5-7 membered ring with the nitrogen of the amide moiety;

or a pharmaceutically acceptable salt thereof.

2. The compound or salt of claim 1 , having a structure of Formula I, II, or III:

3. The compound or salt of claim 2 , having a structure of Formula IA, IIA, or IIIA:

4. The compound or salt of claim 1 , wherein L is

(i) C 1-6 alkylCONR 2 ;

(ii) C 1-6 alkyl-CO 2 R;

(iii) C 1-6 alkyl-NRC(O)R, C 1-6 akllyl-NRC(O)OR, or C 1-6 alkyl-NRC(O)NR;

(iv) X-A; X is a bond, CH 2 , or CH 2 CH 2 ; and A is

(v) C 5-6 cycloalkyl-CONR 2 , C 5-6 cycloalkyl-NRCONR 2 , C 5-6 cycloalkyl-NRCOR, C 5-6 cycloalkyl-COR, or C s-6 cycloalkyl-NR 2 ; or

(vi) L is X-A; X is a bond, CH 2 , or CH 2 CH 2 ; and A is

each R a is independently H or Me; and

each R b is independently H, Me, CMe 3 , (CH 2 CH 2 O) 3 Et, CH 2 O(CH 2 CH 2 O) 2 Et, CH 2 CH 2 OCH 2 CH 2 O(CH 2 ) 3 Me, (CH 2 ) 5 O(CH 2 ) 4 Me, (CH 2 ) 4 O(CH 2 ) 4 Me, CH 2 CH 2 O(CH 2 ) 5 OEt, CH 2 CH 2 OCH 2 CH 2 O(CH 2 ) 4 Me, (CH 2 ) 5 OCH 2 CH 2 OEt, (CH 2 ) 4 OCH 2 CH 2 OEt, CH 2 OCH 2 CH 2 O(CH 2 ) 4 Me, pyrindinyl, or

5. The compound or salt of claim 4 , wherein L is (i) CH 2 CONHMe, CH 2 CONMe 2 , CH 2 CH 2 CONHMe, CH 2 CH 2 CONMe 2 , CH 2 CH(Me)CONHMe, CH 2 CH(Me)CONMe 2 , C(Me)(Et)CONHCH 2 CF 3 , CH 2 CONHCH 2 CO 2 H, CH 2 CH 2 CONHCH 2 CO 2 H, CH 2 CONHCH(Me)CO 2 H, CH 2 CH 2 CONHCH(Me)CO 2 H, CH 2 CONHCH(CH 2 OH)CO 2 H, CH 2 CH 2 CONHCH(CH 2 OH)CO 2 H, CH 2 CONHCH(CH 2 Ph)CO 2 H, CH 2 CH 2 CONHCH(CH 2 Ph)CO 2 H, CH 2 CONHCH(CO 2 H)CH 2 CO 2 H, CH 2 CH 2 CONHCH(CO 2 H)CH 2 CO 2 H, CH 2 CONHCH(CO 2 H)CH 2 CONH 2 , CH 2 CH 2 CONHCH(CO 2 H)CH 2 CONH 2 , CH 2 CONHCH(CO 2 Me)CH 2 CO 2 H, CH 2 CH 2 CONHCH(CO 2 Me)CH 2 CO 2 H, CH 2 CONHCH(CO 2 Me)CH 2 CONH 2 , CH 2 CH 2 CONHCH(CO 2 Me)CH 2 CONH 2 , CH 2 CONHCH 2 CO 2 Me, CH 2 CH 2 CONHCH 2 CO 2 Me, CH 2 CONHCH(Me)CO 2 Me, CH 2 CH 2 CONHCH(Me)CO 2 Me, CH 2 CONHCH(CH 2 OH)CO 2 Me, CH 2 CH 2 CONHCH(CH 2 OH)CO 2 Me, CH 2 CONHCH(CH 2 Ph)CO 2 Me,

CH 2 CONHCH(CO 2 Me)CH 2 CO 2 Me, CH 2 CONHCH(CO 2 H)CH 2 CO 2 Me,

(ii) CH 2 CO 2 H, CH 2 CH 2 CO 2 H, CH═CHCO 2 H, CH 2 CH═CHCO 2 H, CH(CMe 3 )CO 2 H, CH 2 CH(CMe 3 )CO 2 H, CH 2 CH(Me)CO 2 H, CH(Me)CO 2 H, CH(Me)CH 2 CO 2 H, CH 2 CO 2 Me, CH 2 CH 2 CO 2 Me, CH═CHCO 2 Me, CH 2 CH═CHCO 2 Me, CH(CMe 3 )CO 2 Me, CH 2 CH(CMe 3 )CO 2 Me, CH 2 CH(Me)CO 2 Me, CH(Me)CO 2 Me, CH(Me)CH 2 CO 2 Me, CH 2 CO 2 Et, CH 2 CH 2 CO 2 Et, CH═CHCO 2 Et, CH 2 CH═CHCO 2 Et, CH(CMe 3 )CO 2 Et, CH 2 CH(CMe 3 )CO 2 Et, CH 2 CH(Me)CO 2 Et, CH(Me)CO 2 Et, CH(Me)CH 2 CO 2 Et, CH 2 CO 2 CMe 3 , CH 2 CH 2 CO 2 CMe 3 , CH═CHCO 2 CMe 3 , CH 2 CH═CHCO 2 CMe 3 , CH(CMe 3 )CO 2 CMe 3 , CH 2 CH(CMe 3 )CO 2 CMe 3 , CH 2 CH(Me)CO 2 CMe 3 , CH(Me)CO 2 CMe 3 , or CH(Me)CH 2 CO 2 CMe 3 ; or

(iii) CH 2 CH 2 NHCOMe, CH 2 CH 2 NHCO 2 CMe 3 , CH 2 CH 2 NHCONHMe, CH 2 CH 2 NHCO 2 Me, or CH 2 CH 2 NHCONMe 2 .

6. The compound or salt of claim 1 , wherein R is H, Me, Et, or CMe 3 .

7. The compound or salt of claim 1 , wherein

L is

E is CO 2 R a , CONR a R b , NR a R b , NR a CONR a R b , NR a COR a ; or NR a CO 2 R a ;

each R a is independently H, Me, Et, or CMe 3 ; and

each R b is independently H, Me, Et, CH 2 CONHMe, CH 2 CONMe 2 , or CH 2 CONH 2 .

8. The compound or salt of claim 7 , wherein L is

9. The compound or salt of claim 1 , wherein

(i) at least one R 2 is F;

(ii) at least one R 2 is CI; or

(iii) one R 2 is F and the other R 2 is CI or F.

10. The compound or salt of claim 1 , wherein

(i) at least one R 2 is H; or

(ii) each R 2 is H.

11. The compound or salt of claim 1 , wherein at least one R 2 is phenyl, pyridinyl, hydroxyphenyl, CF 3 , —C≡C—CH 2 cyclopropyl, -C≡C-cyclopropyl, furanyl, thienyl, methyl, imidazolyl, CH(CH 3 ) 2 , -(CH 2 ) 2 pyridinyl, -C≡C—(CH 2 ) 2 SCH 3 , CN, —(CH 2 ) 4 SCH 3 , —(CH 2 ) 4 CN, CO 2 H, CONHCH 3 , -C≡C—(CH 2 ) 2 CN, CON(CH 3 ) 2 , CO 2 CH 2 CH 3 , —CH═CH 2 , fluoropyridinyl, chloropyridinyl, or cyanopyridinyl.

12. The compound or salt of claim 1 , wherein R 3 is H.

13. A compound as recited in Table A, or a pharmaceutically acceptable salt thereof:

TABLE A

A1

A2

A3

A4

A5

A6

A7

A8

A9

A10

A11

A12

A13

A14

A15

A16

A17

A18

A19

A20

B1

B2

B3

B4

B5

B6

B7

B8

B9

B10

B11

B12

B13

B14

B15

B16

B17

B18

B19

B20

B21

B22

B23

B24

B25

B26

B27

B28

B29

B30

B31

B32

B33

B34

B35

B36

B37

B38

B39

B40

B41

B42

B43

B44

B45

B46

B47

B48

B49

B50

B51

B100

B52

B53

B54

B55

B56

B57

B58

B59

B60

B61

B62

B63

B64

B65

B66

B67

B68

B69

B70

B71

B72

B73

B74

B75

B76

B77

B78

B79

B80

B81

B82

B83

B84

B85

B86

B87

B88

B89

B90

B91

B92

B93

B94

B95

B96

B97

B98

B99

B101

B102

B103

B109

B120

B121

B122

B123

B124

B125

B126

B127

B128

B129

B130

B131

B132

B133

B134

B135

B136

B137

B138

B139

B140

B141

B142

B143

B144

B145

B146

B147

B148

B149

B150

B151

B152

B153

B154

B160

B161

B162

B163

B164

B165

B166

B167

B168

B169

B170

B171

B172

B173

B174

B175

B176

B177

B178

B179

B180

B181

B182

B183

B184

B185

B186

B187

B188

B189

B190

B191

B192

B193

B194

B195

B196

B197

B198

B199

B200

B201

B202

B203

B204

B205

B206

B207

B208

B209

B210

B211

B212

B213

B214

B215

B216

B217

B218

B219

B220

B221

B222

C1

C2

C3

C4

C5

C6

C7

C8

C9

C10

C11

C12

C13

C14

C15

C16

C17

C18

TABLE B

A1

A2

A3

A4

A5

A6

A7

A8

A9

A10

A11

A12

A13

A14

A15

A16

A17

A18

A19

A20

TABLE C

B1

B2

B3

B4

B5

B6

B7

B8

B9

B10

B11

B12

B13

B14

B15

B16

B17

B18

B19

B20

B21

B22

B23

B24

B25

B26

B27

B28

B29

B30

B31

B32

B33

B34

B35

B36

B37

B38

B39

B40

B41

B42

B43

B44

B45

B46

B47

B48

B49

B50

B51

B100

B52

B53

B54

B55

B56

B57

B58

B59

B60

B61

B62

B63

B64

B65

B66

B67

B68

B69

B70

B71

B72

B73

B74

B75

B76

B77

B78

B79

B80

B81

B82

B83

B84

B85

B86

B87

B88

B89

B90

B91

B92

B93

B94

B95

B96

B97

B98

B99

B101

B102

B103

B109

B120

B121

B122

B123

B124

B125

B126

B127

B128

B129

B130

B131

B132

B133

B134

B135

B136

B137

B138

B139

B140

B141

B142

B143

B144

B145

B146

B147

B148

B149

B150

B151

B152

B153

B154

B160

B161

B162

B163

B164

B165

B166

B167

B168

B169

B170

B171

B172

B173

B174

B175

B176

B177

B178

B179

B180

B181

B182

B183

B184

B185

B186

B187

B188

B189

B190

B191

B192

B193

B194

B195

B196

B197

B198

B199

B200

B201

B202

B203

B204

B205

B206

B207

B208

B209

B210

B211

B212

B213

B214

B215

B216

B217

B218

B219

B220

B221

B222

TABLE D

C1

C2

C3

C4

C5

C6

C7

C8

C9

C10

C11

C12

C13

C14

C15

C16

C17

C18

.

14. A method of treating influenza in a subject in need thereof, comprising administering to said subject a safe and effective amount of a compound or salt of claim 1 .

15. A method of reducing an amount of influenza viruses in a biological sample or in a subject in need thereof, comprising administering to said biological sample or subject a safe and effective amount of a compound or salt of claim 1 .

16. A pharmaceutical composition for treatment of an influenza infection in a subject, comprising a compound or salt of claim 1 and a pharmaceutically acceptable carrier, wherein the composition optionally comprises an additional agent selected from neuraminidase inhibitors, ion channel inhibitors, and polymerase inhibitors.

17. A compound having the structure of:

B143

or a pharmaceutically acceptable salt thereof.

18. A method of treating influenza in a subject in need thereof, comprising administering to said subject a safe and effective amount of the compound or salt of claim 17 .

19. A method of reducing an amount of influenza viruses in a biological sample or in a subject in need thereof, comprising administering to said biological sample or subject a safe and effective amount of the compound or salt of claim 17 .

20. A pharmaceutical composition for treatment of an influenza infection in a subject, comprising the compound or salt of claim 17 and a pharmaceutically acceptable carrier, wherein the composition optionally comprises an additional agent selected from neuraminidase inhibitors, ion channel inhibitors, and polymerase inhibitors.