Method of treating inherited severe neutropenia

1. A method of treating cyclic or severe congenital neutropenia, in a patient in need of such treatment comprising administering a therapeutically effective amount of a compound of Formula (I)

or a pharmaceutically acceptable salt thereof wherein

R 1 is C 1-6 alkyl or C 1-6 alkoxy-C 1-6 alkyl;

M is

(1) hydrogen,

(2) C 1-6 alkyl,

(3) hydroxy C 1-6 alkyl,

(4) halo C 1-6 alkyl,

(5) C 2-6 alkenyl, or

(6) C 1-6 alkoxy-C 1-6 alkyl;

Ra and Rb are each individually

(1) hydrogen,

(2) C 1-6 alkyl,

(3) halo,

(4) carboxy,

(5) C 1-6 alkoxy,

(6) phenyl,

(7) C 1-6 alkylcarbonyl,

(8) di-(C 1-6 alkyl)amino;

(9) hydroxy;

R 2 and R 3 are each independently

(1) hydrogen,

(2) C 1-6 alkyl,

(3) halo,

(4) carboxy,

(5) C 1-6 alkoxy,

(6) phenyl,

(7) C 1-6 alkylcarbonyl,

(8) aminoC 2-3 alkyloxy carbonyl wherein the amino is optionally mono or di-substituted with C 1-6 alkyl,

(9) aminoC 2-3 alkylamino carbonyl wherein the amino is optionally mono or di-substituted with C 1-6 alkyl,

(10) hydroxy,

(11) aminocarbonyl wherein the amino is optionally mono or di-substituted with C 1-6 alkyl,

(12) hydroxymethyl,

(13) aminocarbonyloxy C 1-3 alkyloxy wherein the amino is optionally mono or di-substituted with C 1-6 alkyl,

(14) cyano,

(15) morpholinocarbonylphenyl,

(16) amino wherein the amino is optionally mono or di-substituted with C 1-6 alkyl, with the proviso that R 2 and R 3 may be joined together to form a methylenedioxy group or a furan ring,

(17) morpholinocarbonyl;

R4 is

(a) Q-C(O)—Y—N(R7)(R8), or

(b) Q-C(O)—ORx, where Rx is carboxyC-16alkyl, benzyloxycarbonylC 1-3 alkyl, or t-butoxycarbonylC 1-3 alkyl,

wherein

Q is a covalent bond or —C(R 5 )(R 6 )—

wherein R 5 and R 6 are each individually C 1-3 alkyl or hydrogen,

Y is

or a covalent bond;

R 12 is hydrogen or C 1-3 alkyl;

R 7 and R 8 are each individually

(a) hydrogen,

(b) C 1-6 alkyl,

(c) C 1-6 alkyloxy C 2-3 alkyl,

(d) hydroxy C 2-6 alkyl,

(e) polyhydroxyC 2-6 alkyl,

(f) carboxamido C 1-6 alkyl,

(g) polyacyloxyC 2-6 alkyl

(h) C 1-6 alkanoyl,

(i) substituted phenyl or phenyl C 1-6 alkyl, wherein the substitutent is X 1 as defined immediately below,

(j) C 2-6 alkenyl,

(k) C 6-10 cycloalkenyl,

(l) heteroaryl C 1-6 alkyl wherein the hetero aryl includes pyridinyl, imidazolyl, triazolyl, benzylimidazolyl, and furyl,

(m) carboxy C 1-6 alkyl,

(n) carbo C 1-6 alkoxy C 1-3 alkyl,

(o) phenylsulfonyl,

(p) C 1-6 alkylsulfonyl,

(q) benzyloxy,

(r) morpholinyl C 1-3 alkylsulfonyl,

(s) tetrahydropyranyl,

(t) aminoC 1-3 alkylsulfonyl wherein the amino is optionally mono or di-substituted with C 1-6 alkyl,

(u) aminocarbonyl wherein the amino is optionally mono or di-substituted with C 1-6 alkyl,

(v) aminocarbonyloxyC 2-6 alkyl wherein the amino is optionally mono or di-substituted with C 1-6 alkyl,

(w) azabicyclo of 7 to 12 atoms,

(x) di C 1-3 alkylamino C 2-6 alkyl wherein the amino is optionally mono or di-substituted with C 1-6 alkyl,

(y) bicycloalkyl of 7 to 12 atoms,

(z) C 3-10 cycloalkyl optionally substituted with C 1-6 alkyl,

(aa) pyrazolidinyl,

(bb) substituted piperidinyl or pyrrolidinyl wherein the substitutent is hydrogen, C 1-3 alkyl, hydroxyC 1-3 alkylbenzyl, carboxamido or amino wherein the amino is optionally mono or di-substituted with C 1-6 alkyl,

(cc) substituted pyrrolidinyl wherein the substitutent is carboxamido or amino wherein the amino is optionally mono or di-substituted with C 1-6 alkyl,

(dd) pyrimidinyl,

(ee) N-cyano-N′-phenylamidino,

(ff) phosphonoC 1-6 alkyl, or

(gg) α-C 1-3 alkyl benzyl or mono or di-substituted benzyl or mono or di-substituted pyridylmethyl, wherein the substitutents are X 1 and X 2 ,

wherein

X 1 is

(1) hydrogen,

(2) halo,

(3) C 1-6 alkyl,

(4) halo-C 1-6 alkyl,

(5) C 2-6 alkenyl,

(6) hydroxy-C 1-6 alkyl,

(7) C 1-6 alkylcarbonyl,

(8) C 1-6 alkylcarbonylamino;

(9) CN,

(10) CF 3 ,

(11) CH 3 O,

(12) amino wherein the amino is optionally mono or di-substituted with C 1-6 alkyl;

(13) carboxy, or

(14) phenylsulfonylaminocarbonyl;

X 2 is hydrogen, halo or C 1-6 alkyl;

n is 1, 2, 3, 4 or 5;

R 9 is selected from hydrogen, C 1-4 -alkyl, and C 1-3 alkoxyC 1-3 alkyl; or phenyl, phenyl C 1-3 alkyl, pyridyl, and pyridyl C 1-3 alkyl;

R 10 and R 11 are each independently selected from hydrogen, C 1-4 alkyl, and C 1-3 alkoxyC 1-3 alkyl, or aryl as defined above, or are together oxo; or

wherein R 7 and R 8 are joined together to form mono or di-substituted ring of 4, 5, 6, or 7 atoms or 7 to 12 atoms such as

(1) piperidinyl or homopiperidinyl,

(2) piperazinyl,

(3) morpholinyl, thiomorpholinyl or

1,1-dioxo-4-thiomorpholinyl,

(4) pyrroylidinyl,

(5) pyrryl,

(6) imidazolyl,

(7) triazolyl,

(8) saturated azabicyclo of 7 to 12 atoms,

(9) azaspiro having 3 to 9 carbon atoms, said ring being saturated,

(10) tetrazolyl,

(11) pyrazolidinyl,

(12) dihydrodimethozyisoquinolyl,

(13) azetidinyl, or

(14) diazabicyclo ring of 7-12 atoms,

wherein the substituents are each selected from the group consisting of hydrogen and C 1-3 alkyl, benzyloxycarbonyl, carboxy, phenyl C 1-3 alkyl amino carbonyl, pyrrolidinylmethyl, hydroxy C 1-3 alkyl, C 1-6 alkyloxy, C 1-4 -alkyloxy carbonyl, aminocarbonyl wherein the amino is optionally mono or di-substituted with C 1-6 alkyl, and oxo; or

—N(R7)R8 may be an amino acid residue including natural amino acids such as lysine; or R 8 and R 9 are joined together to form a mono or di-substituted saturated monocyclic ring of 6 to 7 atoms and having two hetero atoms which are the nitrogens to which R 8 and R 9 are attached;

said rings to include piperazinyl and homopiperazinyl; or R 9 and R 10 are joined together to

form a mono or di-substituted monocyclic saturated ring of 5 to 7 atoms and having one hetero atom which is the nitrogen to which R 9 is attached; or

wherein R 9 and R 12 are joined together to form a mono or di-substituted saturated monocyclic ring of 5, 6; or 7 atoms, said ring having one hetero atom which is the nitrogen to which R 9 is attached; or wherein R 10 and R 12 are joined together to form a mono or di-substituted saturated monocyclic ring of 5, 6, or 7 carbon atoms; or

wherein R 8 and R 11 are joined together to form a mono or di-substituted saturated monocyclic ring of 5, 6, or 7 atoms, said ring having one hetero atom which is the nitrogen to which R 8 is attached; and the substituents are independently selected from Hydrogen and C 1-3 alkyl, thereby treating cyclic or severe congenital neutropenia in a patient in need of such treatment.

2. The method according to claim 1 where wherein

R is C 1-6 alkyl;

R 1 is C 1-6 alkyl or C 1-6 alkoxy-C 1-6 alkyl;

M is

(1) hydrogen,

(2) C 1-6 alkyl,

(3) hydroxy C 1-6 alkyl,

(4) halo C 1-6 alkyl,

(5) C 2-6 alkenyl, or

(6) C 1-6 alkoxy-C 1-6 alkyl;

Ra is

(1) hydrogen,

(2) C 1-6 alkyl,

(3) halo,

(4) carboxy,

(5) C 1-6 alkoxy,

(6) phenyl,

(7) C 1-6 alkylcarbonyl,

(8) amino wherein the amino is optionally mono or di-substituted with C 1-6 alkyl;

Rb is hydrogen, or C 1-6 alkyl,

R 2 and R 3 are each independently

(1) hydrogen,

(2) C 1-6 alkyl,

(3) halo,

(4) carboxy,

(5) C 1-6 alkoxy,

(6) phenyl,

(7) C 1-6 alkylcarbonyl,

(8) amino wherein the amino is optionally mono or di-substituted with C 1-6 alkyl, or with the proviso that R 2 and R 3 may be joined together to form a methylenedioxy group or a furan ring;

R 4 is

(a) Q-C(O)—Y—N(R 7 )(R 8 ), or

(b) Q-C(O)—ORx, where Rx is carboxy-C-16alkyl, benzyloxycarbonylC 1-3 alkyl, or t-butoxycarbonylC 1-3 alkyl,

wherein

Q is a covalent bond or —C(R 5 )(R 6 )—

wherein R 5 and R 6 are each individually C 1-3 alkyl or hydrogen,

Y is

or a covalent bond;

R 12 is hydrogen or C 1-3 alkyl;

R 7 and R 8 are each individually

(a) hydrogen,

(b) C 1-6 alkyl,

(c) C 1-6 alkyloxy C 2-3 alkyl,

(d) hydroxy C 2-6 alkyl,

(e) carboxamido C 1-6 alkyl,

(f) C 1-6 alkanoyl,

(g) substituted phenyl or phenyl C 1-6 alkyl wherein the substitutents are X 1 , and X 2

(h) C 2-6 alkenyl,

(i) C 6-10 cycloalkenyl,

(j) heteroaryl C 1-6 alkyl wherein the hetero aryl includes pyridinyl, imidazolyl, triazolyl, benzylimidazolyl, and furyl,

(k) carboxy C 1-6 alkyl,

(l) C 1-6 alkylsulfonyl,

(m) carboC 1-6 alkyloxyC 2-3 alkyl,

(n) morpholinyl C 1-3 alkylsulfonyl,

(o) aminoC 1-3 alkylsulfonyl wherein the amino is optionally mono or di-substituted with C 1-6 alkyl,

(p) aminocarbonyl wherein the amino is optionally mono or di-substituted with C 1-6 alkyl,

(q) aminocarbonyloxyC 1-6 alkyl wherein the amino is optionally mono or di-substituted with C 1-6 alkyl,

(r) di C 1-3 alkylamino C 1-6 alkyl wherein the amino is optionally mono or di-substituted with C 1-6 alkyl,

(s) pyrazolidinyl,

(t) substituted piperidinyl as defined above,

(u) substituted pyrrolidinyl as defined above,

(v) pyrimidinyl,

(w) benzyloxy,

(x) C 3-10 cycloalkyl,

(z) α-C 1-3 alkyl benzyl or mono or di-substituted benzyl or mono or di-substituted pyridylmethyl, wherein the substitutents are X 1 and X 2 ,

wherein

X 1 is

(1) hydrogen,

(2) halo,

(3) C 1-6 alkyl,

(4) halo-C 1-6 alkyl,

(5) C2-6alkenyl,

(6) hydroxy-C 1-6 alkyl,

(7) C 1-6 alkylcarbonyl,

(8) C 1-6 alkylcarbonylamino;

(9) di-C 1-3 alkylamino; or

(10) carboxy,

X 2 is hydrogen, halo or C 1-6 alkyl;

n is 1, 2, 3, 4or 5;

R 9 is selected from hydrogen, C 1-4 alkyl, and C 1-3 alkoxyC 1-3 alkyl; R 10 and R 11 are each independently selected from hydrogen, C 1-4 alkyl, and C 1-3 alkoxy C 1-3 alkyl; or

wherein R 7 and R 8 are joined together to form mono or di-substituted ring of 4, 5, 6, or 7 atoms such as

(1) piperidinyl,

(2) piperazinyl,

(3) morpholinyl,

(4) pyrroylidinyl,

(5) pyrryl,

(6) imidazolyl,

(7) triazolyl,

(8) tetrazolyl,

(9) pyrazolidinyl,

(10) azetidinyl,

wherein the substituents are each selected from the group consisting of hydrogen and C 1-3 alkyl, benzyloxycarbonyl, carboxy, phenyl C 1-3 alkyl amino carbonyl, pyrrolidinyl, methyl, hydroxy C 1-3 alkyl, C 1-6 alkyloxy, C 1-4 alkyloxy carbonyl, and oxo; or R 8 and R 9 are joined together to form a saturated ring of 5 to 7 atoms and having two hetero atoms; or R 9 and R 10 are joined together to form a saturated ring of 5 to 7 atoms and having one hetero atom; or wherein R 9 and R 12 are joined together to form a ring of 5, 6, or 7 atoms, said ring being saturated; or wherein R 10 and R 12 are joined together to form a ring of 5, 6, or 7 atoms, said ring being saturated; or wherein R 8 and R 11 are joined together to form a ring of 5, 6, or 7 atoms, said ring being saturated and having one hetero atom.

3. The method according to claim 1 wherein

R is C 1-3 alkyl;

R 1 is C 1-3 alkyl;

M is

(a) C 1-6 alkyl, or

(b) C 2-6 alkenyl;

R 2 is

(a) hydrogen,

(b) C 1-6 alkyl, or C 1-6 alkoxy, and

R 3 is hydrogen, or R 2 and R 3 are joined together to form a methylenedioxy group or a furan ring;

R 5 and R 6 are each individually hydrogen or C 1-3 alkyl;

R 7 and R 8 are each independently selected from

(a) hydrogen,

(b) C 1-3 alkyl,

(c) C 1-3 alkoxy C 2-3 alkyl,

(d) C 3-7 cycloalkyl,

(e) hydroxyC 2-3 alkyl,

(d) carbo C 1-4 alkyloxymethyl,

(g) substituted benzyl wherein the substituents are X 1 and X 2

wherein X 1 is hydrogen and X 2 is

(1) hydrogen,

(2) halo, or

(3) C 1-3 alkyl;

n is 1, 2 or 3, and

R 9 , R 10 and R 11 are each independently selected from hydrogen, C 1-4 alkyl, and C 1-3 alkoxy C 1-3 alkyl; or

R 7 and R 8 are joined together to form a substituted ring selected from

(a) piperidinyl,

(b) piperazinyl, and

(c) morpholinyl;

or

R 8 and R 9 are joined together to form a ring of 6 to 7 atoms and having two hetero atoms; R 9 and R 10 are joined together to form a saturated ring of 5 to 7 atoms and having one hetero atom; or wherein R 9 and R 12 are joined together to form a ring of 5, 6, or 7 atoms, said ring being saturated; or wherein R 10 and R 12 are joined together to form a ring of 5, 6, or 7 atoms, said ring being saturated; or

wherein R 8 and R 11 are joined together to form a ring of 5, 6, or 7 atoms, said ring being saturated and having one hetero atom.

4. The method of treating cyclic or severe congenital neutropenia in a patient in need of such treatment comprising the administration of a compound according to claim 3 .

5. The method according to claim 1 wherein

Q is a covalent bond;

R is methyl or ethyl;

R 1 is methyl or ethyl;

M is

(a) C 1-4 alkyl, or

(b) C 2-3 alkenyl;

R 2 is

(a) hydrogen,

(b) C 1-3 alkyl, or C 1-3 alkoxy, and

R 3 is hydrogen, or

R 2 and R 3 are joined together to form a furan or dioxacyclopentane ring;

n is 1 or 2;

R 9 and R 10 are each independently selected from

(a) C 1-3 alkyl,

(b) C 1-3 alkoxy C 1-3 alkyl,

(c) hydrogen,

R 7 and R 8 are each independently selected from

(a) C 1-3 alkyl,

(b) C 1-3 alkoxy C 2-3 alkyl,

(c) hydrogen,

(d) hydroxyethyl,

(e) carboethoxymethyl,

(f) cyclopropyl,

or

R 7 and R 8 are joined together to form a substituted ring selected from

(a) piperidinyl, and

(b) morpholinyl, or

R 8 and R 9 are joined together to form a piperazine ring.

6. The method of treating cyclic or severe congenital neutropenia in a patient in need of such treatment comprising the administration of a compound according to claim 5 .

7. The method according to claim 1 wherein the severe neutropenia is cyclic neutropenia (CN) or severe congenital neutropenia (SCN).

8. A method of treating cyclic or severe congenital neutropenia, in a patient in need of such treatment comprising administering a therapeutically effective amount of a compound of Formula Ia

or a pharmaceutically acceptable salt thereof, wherein

R is selected from the group

No.

R

242

—CH3

243

4-fluorophenyl

244

3-chlorophenyl

245

Phenyl

246

Benzyl

247

H

248

i-propyl

249

i-butyl

250

—CH 2 CO 2 Et

251

—CH 2 CO 2 H

252

Et

253

Pr

254

2-pyrimidinyl

255

—CH 2 CH 2 OC(O)NHCH 3

256

Cyclopropyl

256a

—CH 2 CH 2 OH

thereby treating cyclic or severe congenital neutropenia, in a patient in need of such treatment.

9. A method of treating cyclic or severe congenital neutropenia, in a patient in need of such treatment comprising administering a therapeutically effective amount of a compound of Formula Ib

or a pharmaceutically acceptable salt thereof, wherein

No.

n

R

257

1

—NH 2

258

1

4-morpholinyl

259

1

—N(CH 3 )CH 2 CH 2 N(CH 3 ) 2

260

0

—N(CH 3 )CH 2 CH 2 N(CH 3 ) 2

261

0

—N(Et) 2

262

0

—N(CH 3 )(n-butyl)

263

0

4-methyl-1-piperazinyl

264

0

—N(CH 3 )CH 2 CH 2 N(CH 3 )CH 2 Ph

265

0

—CH 2 CO 2 Et

265a

0

1-piperazinyl

265c

0

4-(2-hydroxyethyl)-1-

piperazinyl

265d

0

4-morpholinyl

thereby treating cyclic or severe congenital neutropenia, in a patient in need of such treatment.