(Us); shaunR- Stuff“ 150 M85383? Z133;

127 Pages·2013·4.63 MB·English

US008114887B2
(12) United States Patent (10) Patent No.: US 8,114,887 B2
Barrow et a]. (45) Date of Patent: Feb. 14, 2012
(54) SPIROPIPERIDINE COMPOUNDS USEFUL 4,066,615 A * 1/1978 Murayama et a1~
AS BETA-SECRETASE INHIBITORS FOR THE 2 giléllllgfjtt :11 ~~~~~~~~~~~~~~~~ ~~ 514/278
TREATMENT OF ALZHEIMER’S DISEASE 538523029 A 12/1998 Fisher et a1‘
_ 7,049,321 B2 5/2006 Fisher et al.
(75) Inventors: James C. Barrow, Harleysvllle, PA 2004/0067950 A1 4/2004 Tulshian @131,
(US); Craig A. Coburn; Royersford; PA 2006/0052406 A1 3/2006 Fisher et al.
(US); Melissa S. Egbertson, Ambler, PA FOREIGN PATENT DOCUMENTS
(US); Georgia B. McGaughey,
Harleysville, PA (US); Melody A. DE 2126187 12/1971
_ DE 10012859 9/2000
AMcnWnhee lN‘etilesro,n , Sellersvllle, PA (US);L 011 GB 0 1354313 5/1974
Kenneth E. Rittle, Green Lane, PA JP 46022105 6/1971
(US); Harold G. Selnick, Ambler, PA JP 48016984 7/1973
(Us); shaunR- Stuff“ 150 M85383? Z133;
Schwenksville, Zhi-Qiang W0 WO 99/65494 12/1999
Yang, Schwenksvllle, PA (US); Wenjin W0 W0 03/057698 7/2003
Yang, Foster City, CA (US); Wanli Lu, W0 WO 2004/037800 5/2004
FBousrthenrg Caimtye,, CA (US) Bruce Fahr,
DorWald, Side Reactions in Organic Synthesis, Preface 2005*
(73) Assignees: Merck, Sharp & Dohme Corp., DOW/111d, Side reactions, pp 8 and 9 , 2005*
RahWay, N] (Us); sunesis “Neuroscience Drug Discovery,” presented at Vanderbilt University
Pharmaceuticals Inc South San Pharmacology Department Seminar (Feb. 18, 2008).
- ’ I’ Brana, et al., J. Heterocyclic Chem., 27, 397 “Reaction of N-[(a
Franclsco’ CA (Us) acetoXy)-4-pyridylmethyl]-3,5-dimethylbenzamide With Alkyl
( * ) Notl.c e: Subje. ct' to any d1. scla1. mer,~ the term of thi. s CIshoecr ?a nRaetgeiss”t r1y9 N88O.‘ 29096_07_9 (1984)‘
patent is extended or adjusted under 35 Chem Registry No‘ 128221954 (1990)‘
U~S~C- 15403) by 976 days- CAS Registry No. 150358-83-1 (Interchim Intermediates) (Jul.
2002).
(21) Appl. No.: 11/663,388 _ _
* c1ted by examlner
(22) PCT Filed: Oct. 12, 2005 _ _
Primary Examiner * R1ta Desa1
(86) PCT No.: PCT/US2005/036752 (74) Attorney, Agent, or Firm * Keith D. MacMillan;
§ 371 (OX1), Gerard M. Devl1n
(87) PCT Pub. NO..- W02006/044497 Th e P resent i' nventi' on i' s d'i recte d to S P'n o P'1 P en' d'1 ne com
pounds of formula (1)
PCT Pub. Date: Apr. 27, 2006
(65) Prior Publication Data (1)
US 2007/0197571 A1 Aug. 23, 2007 \//Z
X
Related U.S. Application Data 1 /
R\ N\ 2
(60) Provisional application No. 60/618,420, ?led on Oct. g R
13, 2004.
(51) Int. C]. N
A61K 31/438 (2006.01) |
C07D 411/02 (2006.01) R3
(52) U.S. Cl. ........................................ .. 514/278; 546/18
(58) Field of Classi?cation Search .................. .. 546/18; Which are inhibitors of the beta-secretase enzyme and that are
514/290 useful in the treatment of diseases in Which the beta-secretase
See application ?le for complete search history. enzyme is involved, such as Alzheimer’s disease. The inven
tion is also directed to pharmaceutical compositions compris
(56) References Cited ing these compounds and the use of these compounds and
compositions in the treatment of such diseases in Which the
U.S. PATENT DOCUMENTS beta-secretase enzyme is involved.
3,542,729 A 11/1970 Murayama et al.
3,639,409 A 2/1972 Murayama et al. 11 Claims, No Drawings
US 8,114,887 B2
1 2
SPIROPIPERIDINE COMPOUNDS USEFUL [3-secretase or BACE, thus preventing the formation of
AS BETA-SECRETASE INHIBITORS FOR THE insoluble AB and arresting the production of AB.
TREATMENT OF ALZHEIMER’S DISEASE
SUMMARY OF THE INVENTION
CROSS-REFERENCE TO RELATED
APPLICATIONS The present invention is directed to novel spiropiperidine
compounds represented by general formula (I)
This application claims priority under 35 U.S.C. §119(e) of
US. provisional application Ser. No. 60/618,420, ?led Oct.
(I)
13, 2004.
7%
REFERENCE TO JOINT RESEARCH
AGREEMENT l
R \ N\ R2
H
This invention Was made as a result of activities undertaken
Within the scope of a Joint Research Agreement betWeen
Merck & Co., Inc. and Sunesis Pharmaceuticals, Inc. N
|
FIELD OF THE INVENTION R3
20
The invention is directed to compounds useful as inhibitors or its tautomer (I')
of the beta secretase enzyme, and useful in the treatment of
diseases in Which the beta secretase enzyme is involved, such
as Alzheimer’s Disease. 25 Z (1')
X, <
BACKGROUND OF THE INVENTION
R1 / N
Alzheimer’s disease is characterized by the abnormal \N \R2
deposition of amyloid in the brain in the form of extra-cellular 30
plaques and intra-cellular neuro?brillary tangles. The rate of
amyloid accumulation is a combination of the rates of forma
N
tion, aggregation and egress from the brain. It is generally |
accepted that the main constituent of amyloid plaques is the 4 R3
kD amyloid protein ([3A4, also referred to as A6, [3-protein 35
and BAP) Which is a proteolytic product of a precursor protein and pharmaceutically acceptable salts thereof, Which are use
of much larger size. The amyloid precursor protein (APP or
ful as inhibitors of the [3-secretase enzyme.
ABPP) has a receptor-like structure With a large ectodomain, The invention is also directed to pharmaceutical composi
a membrane spanning region and a short cytoplasmic tail. The
tions Which include an effective amount of a compound of
A6 domain encompasses parts of both extra-cellular and 40 formula (I), or pharmaceutically acceptable salts thereof, and
transmembrane domains of APP, thus its release implies the
a pharmaceutically acceptable carrier. The invention is also
existence of tWo distinct proteolytic events to generate its
directed to methods of treating mammals for diseases in
NH2- and COOH-terminiAt least tWo secretory mechanisms
Which the [3-secretase enzyme is involved, such as Alzhe
exist Which release APP from the membrane and generate
imer’s disease, and the use of the compounds and pharma
soluble, COOH-truncated forms of APP (APPS). Proteases 45 ceutical compositions of the invention in the treatment of
that release APP and its fragments from the membrane are
such diseases.
termed “secretases.” Most APPS is released by a putative
ot-secretase Which cleaves Within the AB protein to release
DETAILED DESCRIPTION OF THE INVENTION
(X-APPS and precludes the release of intact AB. A minor por
tion of APPS is released by a [3-secretase (“B-secretase”), 50 In one embodiment, the present invention is directed to
Which cleaves near the NHZ-terminus of APP and produces methods of treating mammals for diseases in Which the
COOH-terminal fragments (CTFs) Which contain the Whole
[3-secretase enzyme is involved, such as Alzheimer’ s disease,
AB domain. by administering a compound of formula (I)
Thus, the activity of [3-secretase or [3-site amyloid precur
sor protein-cleaving enzyme (“BACE”) leads to the cleavage 55
of APP, production of AB, and accumulation of [3 amyloid
plaques in the brain, Which is characteristic of Alzheimer’s
disease (see R. N. Rosenberg, Arch. NeuroL, vol. 59, Septem
ber 2002, pp. 1367-1368; H. Fukumoto et al, Arch. Neurol,
vol. 59, September 2002, pp. 1381-1389; J. T. Huse et al, J. 60
Biol. Chem, vol 277, No. 18, issue of May 3, 2002, pp.
16278-1 6284; K. C. Chen andW. J. HoWe, Biochem Biophys.
Res. Comm, vol. 292, pp 702-708, 2002). Therefore, thera
peutic agents that can inhibit [3-secretase or BACE may be
useful for the treatment of Alzheimer’s disease. 65
The compounds of the present invention are useful for
treating Alzheimer’s disease by inhibiting the activity of
US 8,114,887 B2
or its tautomer (1')
(1')
15
and pharmaceutically acceptable salts thereof, and individual
enantiomers and diastereomers thereof, Wherein:
X is CR5 or N;
Wherein n is 0, 1 or 2;
X‘ is CRSH or NH; R2 is selected from the group consisting of
Z is O or S; (1) hydrogen,
R1 is selected from the group consisting of (2) ‘Cl-6 alkyl,
(1) hydrogen, (3) iCO_6 alkyl-C3_l 2 carbocyclic, Wherein the carbocy
(2) ‘Cl-6 alkyl, clic group optionally has from one to three ring het
(3) ‘CO-6 a1ky1'C6-10 aryl, eroatoms selected from the group consisting of S, N
(4) 4C06 alkyl-C5_l2 heteroaryl, 25 and O,
(5) 4C06 alkyl-C3_ 12 carbocyclic, Wherein the carbocy (4) iCO-6 a1ky1'C6-10 aryl,
clic group optionally has from one to three ring het
eroatoms selected from the group consisting of S, N (6) iCO_6 alkyl-C5_l2 heteroaryl,
and O, Wherein said R2 alkyl moiety is optionally substituted
(6) 4OiR6, and 30 With one or more
(a) halogen
Wherein said Rl alkyl moiety is optionally substituted (b) cyano
With one or more (c) 4C3_8 cycloalkyl
(a) iOR4, (d) iO%l_6alkyl,
(b) halogen, 35 (6) OH,
(c) cyano, and and said R2 cycloalkyl moiety is optionally substituted
(d) iNR4R4', With one or more ‘CL6 alkyl,
said Rl carbocyclic moiety is optionally substituted and said R2 aryl or heteroaryl moiety is optionally sub
With one or more stituted With one or more
(a) iOR“, 40 (a) iORlO,
(b) :0, (b) halogen,
(c) halogen, (c) -cyano,
(d) cyano, ((1) *NO»
(e) iC(:O)iNR4R4Y, (6) 'Q4'C1-6 alkyl,
(l) iCL6 alkyl, Wherein said alkyl is optionally sub (1) ‘CL6 alkyl, Wherein said alkyl is optionally sub
stituted With one or more stituted With one or more
(I) halogen, (I) halogen, and
(H) ‘OH, and (II) cyano,
(Ill) iC6_1O aryl, (g) iCO_3 alkyl-C6_1O aryl, Wherein said aryl is
(g) iNR4iSO2iR4', 50 optionally substituted With one or more
(h) isoziR‘l, (I) halogen,
(i) iNR4%(:O)iR4', (H) ‘Cl-6 alkyl,
(i) %(:O)%3R4, (Ill) iC2_6 alkenyl,
(k) iNR4R4', (IV) iC2-6 alkynyl,
(l) %(:O)iR4, and 55 (V) 4OiCl-6 alkyl,
(m) iSO2iNR4R4', (VI) iSO2iCl_6 alkyl,
and said Rl aryl and heteroaryl moieties are optionally (V H) cyano,
substituted With one or more (V 111) iC3_8 cycloalkyl,
(a) halogen, (IX) *NOZ,
(b) iCl-6 alkyl, 60 Qi) iSO2iNR4R4R4'
(c) iC2_6 alkenyl, (h) iSO2%l_6 alkyl,
(d) iC2-6 alkynyl, (i) iSO2iNR4R4',
(e) ‘Co-3 a1ky1'C6-10 aryl’ iNR4R4's
(f) cyano, (k) iC3_8 cycloalkyl,
(g) 4oico-s a1ky1'C6-10 aryl, 65 (1) 4C26 alkenyl,
(h) iOiR“, (m) iNHC(:O)iCl_6 alkyl, Wherein said alkyl is
(i) %(:O)iNR4R4Y, optionally substituted With one or more
US 8,114,887 B2
6
(I) iNR4R4' (IV) halogen,
(II) OH (V) cyano,
(III) iSOZR“, and (VI) iC3_8 cycloalkyl, and
(IV) iNHSO2R4, (VII) N02,
(n) iNHC(:O)iCO_3 alkyl-C6_1O aryl, wherein 5 and R12 is selected from the group consisting of
said aryl is optionally substituted With one or more (I) hydrogen,
(I) NR4R4', (H) iCl-6 alkyl,
(II) OH, (III) 4C}6 alkenyl,
(III) iSOZR“, and (IV) 4C}6 alkynyl,
(IV) iNHSO2R4, (V) 4C}8 cycloalkyl, and
(0) 4C03 all<yl-C5_l2 heteroaryl, Wherein said het (VI) ‘Co-3 a1ky1'C6-10 aryl,
eroaryl is optionally substituted With one or more and said Rl2 alkyl, alkenyl and alkynyl moiety is
(I) halogen, optionally substituted With one or more
(II) iCL6 alkyl, and (A) halogen,
(III):O, (B) hydroxyl,
(C) cyano,
(D) 4OiCl_6 alkyl, Wherein said alkyl is option
ally substituted With one or more halogen,
(E) iNR4R4',
(t) 4OiC2_6 alkenyl, 20 (F) iNR4iS(:O)2iR4',
andm is 0, l or 2; (G) iNR4%(:O)iR4',
and Q3 and Q4 are selected from the same group as Q1 (H) iNR4%(:O)ADR4Y,
and Q2; (I) *S(:O)2*NRL,
R3 is selected from the group consisting of and said R1O cycloalkyl moiety is optionally sub
(1) hydrogen,
25 stituted With one or more
(2) ico-s a1ky1'C6-10 aryl, (A) halogen,
(3) iCO_3 alkyl-C5_l2 heteroaryl, (B) hydroxyl,
(4) iCO_3 alkyl-C3_ 1O carbocyclic, Wherein the carbocyclic (C) -cyano,
group optionally has from one to three ring heteroatoms (D) iO4Cl_6 alkyl, and
selected from the group consisting of S, N and 0, 30 (E) iCL6 alkyl, Wherein said alkyl is optionally
wherein said R3 alkyl moiety is optionally substituted With substituted one or more halogen;
and said Rl2 aryl moiety is optionally substituted
one or more
(a) ‘0R1 1,
With one or more
(b) halogen, (A) halogen,
(C) cyano, 35 (B) cyano,
(C) iO4Cl_6 alkyl, and
(D) ‘CL6 alkyl, Wherein said alkyl is optionally
substituted one or more halogen;
and said R3 cycloalkyl moiety is optionally substituted Q5 and Q6 are selected from the same group as Q1 and Q2;
With one or more 40 R4 and R4’ are selected from the group consisting of
(a) ‘Cl-6 alkyl, (1) hydrogen,
(2) ‘CL8 alkyl, Wherein said alkyl is optionally substi
and said R3 aryl and heteroaryl moiety is optionally sub tuted With
(a) halogen,
stituted With one or more
(a) 40R”, 45 (b) 4C}8 cycloalkyl
(b) iNR4R4', (c) 4CO2CL6 alkyl
(c) halogen, (d) iOCL6 alkyl, Wherein said alkyl is optionally sub
(d) cyano, stituted With one or more
(n ANOZ, (I) halogen, or
(g) Q6-R4, and 50 (II) cyano,
(h) iCL6 alkyl, Wherein said alkyl is optionally substi (3) 4C28 alkenyl, and
tuted With one or more (4) ‘Co-3 a11<y1-C6_10ary1;
(I) halogen, R5 is selected from the group consisting of
(II) cyano, (1) hydrogen,
(III) ‘CL6 alkyl, (2) iCl-6 alkyl,
(IV) ADiCL6 alkyl, (3) halogen, and
(4) iCOZiR“,
R6, R7, R8, R9, R10 and R11 are independently selected from
(i) 4C}6 alkenyl, the group consisting of:
4C2-6 alkynyl, 60 (1) hydrogen,
(k) 4C03 all<yl-C5_l2 heteroaryl, (2) iCl-6 alkyl,
(1) 4C26 alkenyl, (3) iC3_8 cycloalkyl,
(m) iCO_3 alkyl-C6_1O aryl, Wherein said aryl moiety is (4) ‘Co-3 a1ky1'C6-10 aryl’
optionally substituted With one or more Wherein said alkyl is optionally substituted With one or
(I) ‘Cl-6 alkyl, 65 more
(II) 4C}6 alkenyl, (A) halogen,
(III) 4C}6 alkynyl, (B) hydroxyl,
US 8,114,887 B2
7 8
(C) cyano, When R2 is 4C03 alkyl-C6_1O aryl, preferably the aryl
(D) 4OiCl_6 alkyl, wherein said alkyl is optionally moiety is optionally substituted With one or more
substituted With one or more halogen, (a) iORlo,
and said cycloalkyl and aryl are optionally substituted (b) halogen,
With one or more (c) ‘CL6 alkyl, Wherein said alkyl is optionally substi
(A) halogen,
tuted With one or more
(B) hydroxyl,
(I) halogen,
(C) cyano,
(II) cyano,
(D) 4O4Cl_6 alkyl, and (III) iCMalkyl,
(E) iCl_6 alkyl, Wherein said alkyl is optionally substi
(IV) iO4C1_6 alkyl,
tuted one or more halogen. (V) 4C3_8 cycloalkyl,
The invention is also directed to pharmaceutical composi
(v1) *C(:O)*C1.6 alkyl,
tions Which include an effective amount of a compound of
(d) iCO_3 alkyl-C6_1O aryl, Wherein said aryl moiety is
formula (I), or pharmaceutically acceptable salts thereof, and
a pharmaceutically acceptable carrier. optionally substituted With one or more
(I) iCl-6 alkyl,
The present invention is further directed to a method for the
(II) 4C}6 alkenyl,
manufacture of a medicament or a composition for inhibiting
(III) iC2_6 alkynyl,
[3-secretase enzyme activity in humans and animals. The
(IV) halogen,
invention is also directed to a method for the manufacture of
a medicament for the treatment of AlZheimer’s Disease in 20 (V) cyano,
humans, comprising combining a compound of the present (VI) iC3_8 cycloalkyl,
invention With a pharmaceutical carrier or diluent. (v11) N02,
In another embodiment, the invention is directed to novel (e) iSO2iCL6 alkyl, and
spiropiperidine compounds of formula (I) above, provided (f) iNHC(:O)4Cl_6 alkyl, Wherein said alkyl is option
that When X is N; Z is O; R1 is unsubstituted cyclohexyl; and 25 ally substituted With one or more
R2 is unsubstituted phenyl, then R3 is not unsubstituted ben (I) iNR4R4', and
Zyl. (II) ADH.
In a preferred embodiment, Z is O. Within this embodiment, there is a sub-genus of com
In one sub-genus of this embodiment, the invention is pounds of formula (II)
directed to compounds of formula (I) Wherein X is N and X' 30
is NH. In another embodiment, X is CR5, Wherein R5 is
preferably hydrogen, and X' is CR5 H, Wherein R5 is prefer (II)
ably hydrogen.
7% i”
In another embodiment of the compounds of formula (I),
R1 is ‘CL6 alkyl or 4C03 alkyl-C3_ 12 carbocyclic Wherein 35 R1\ N / \
said alkyl or carbocyclic is optionally substituted With one or
N
H
more
(a) iOR4, \
(b) halogen,
(c) cyano, 40 N|
(d) iNR4R4', and R3
(e) iCL6 alkyl.
Preferred Rl carbocyclic groups include-C3_8 carbocyclic
or its tautomer (II')
groups, including cyclobutyl, cyclopentyl, cyclohexyl, mor
pholinyl, tetrahydropyran and pyrrolidinyl.
45
In another embodiment of the compounds of formula (I),
(11')
R1 is iCO_3 alkyl iC6_1O aryl, preferably phenyl or benZyl. Z
Preferably, the R1 aryl moiety is optionally substituted With Xr4( R15
one or more
(a) halogen, or 50 Rl\ / N / / \
(b) iCL6 alkyl. N
In another embodiment, R1 is CO_3 alkyl-C5_ 12 heteroaryl, \
Wherein the heteroaryl moiety is optionally substituted With
one or more N
(a) halogen, or 55 |
(b) iCL6 alkyl. R3
Preferred Rl heteroaryl groups include pyridinyl, thienyl,
furanyl and imidaZolyl. and pharmaceutically acceptable salts thereof, and individual
In another embodiment, R2 is selected from the group enantiomers and diasteromers thereof, Wherein X, X', Z, R1
consisting of 60 and R3 are as de?ned above, and R15 is selected from the
(1) iCl-6 alkyl, group consisting of
(2) iCO_6 all<yl-C3_8 carbocyclic, and (a) iORlO,
(3) 4C03 alkyl-C6_1O aryl, Which are optionally substi (b) halogen,
tuted as described above. (c) -cyano,
Preferably, R2 is selected from iCL6 alkyl, phenyl, benZyl, 65
or iCO_3 all<yl-C3_8 carbocyclic, optionally substituted as (e) ‘CL6 alkyl, Wherein said alkyl is optionally substi
described above. tuted With one or more
US 8,114,887 B2
1 0
(I) halogen, and dihydroindolyl and pyridyl. Preferably, When R3 is 4C03
(II) cyano, alkyl-heteroaryl, the heteroaryl is substituted With one or
(f) iCO_3 all<yl-C6_1O aryl, wherein said aryl is optionally
more
substituted With one or more (a) iORlz,
(I) halogen, (b) halogen,
(H) iCl-6 alkyl, (c) cyano,
(V) iO4Cl-6 alkyl,
(VI) isozicm alkyl, (e) ‘CL6 alkyl, and
(VII) cyano,
(VII) iC3_8 cycloalkyl, In preferred embodiments of compounds of formula (II), X
Qi) iSO2iNR4R4' is N and Z is O.
(g) iSO2iCl-6 alkyl, In another sub-genus of the embodiment of compounds of
(h) iSO2iNR4R4', formula (I), the invention is directed to compounds of formula
(i) iC3_8 cycloalkyl, (III):
(j) iNHC(:O)iCl_6 alkyl, Wherein said alkyl is option
ally substituted With one or more
(I) iNR4R4' (111)
(II) OH
(III) iSOZR“, and X
20
(IV) iNHSO2R4, R1\N / N\R2
(k) 4C03 alkyl-C5_l2 heteroaryl, Wherein said heteroaryl
H
is optionally substituted With one or more
(I) halogen,
(II) iCL6 alkyl, and 25 )N 3
(III):O,
(1) iS(:O)miCO-6 a1ky1'C6-10 ary 1:
(m) %O2iR4, |
(n) iC(:O)iNR4R4',
/\/Rl6
(o) iCO_6 alkyl-NR4SO2iR4. 30
Within this sub-genus of compounds of formula (II), R3 is
preferably
(1) iCO_3 all<yl-C6_1O aryl, or or its tautomer (III')
(2) iCO_3 alkyl-C5_l2 heteroaryl,
35
and said aryl and heteroaryl are optionally substituted With
(111')
one or more MZ
(a) iORlz,
(b) iNR4R4',
(c) halogen, RI\N/ N\R2
40
(d) cyano,
(1) *N02,
(g) -Q6-R4, and
(h) ‘CL6 alkyl, Wherein said alkyl is optionally substi N
tuted With one or more 45
(I) halogen,
\
(II) cyano, |
(III) %l_6 alkyl,
/\/Rl6
(IV) A)%l_6 alkyl,
(V) iC3_8 cycloalkyl,
50
(V1) %(:O)C1_6 alkyl,
(i) iC2_6 alkenyl, and pharmaceutically acceptable salts thereof, and individual
iC2-6 alkynyl, enantiomers and diastereomers thereof, Wherein X, X', Z, R1,
(k) iCO_3 alkyl-C5_l2 heteroaryl, and R2 are as de?ned above, and R16 is selected from the
(1) 4C03 alkyl-C6_1O aryl, and said aryl moiety is option 55 group consisting of
ally substituted With one or more (a) iORlz,
(I) ‘Cl-6 alkyl,
(II) iC2_6 alkenyl, (c) halogen,
(III) 4C}6 alkynyl, (d) cyano,
(IV) halogen, 60 (f) iNOZs
(V) cyano, (g) -Q6-R4, and
(VI) 4C}8 cycloalkyl, and (h) ‘CL6 alkyl, Wherein said alkyl is optionally substi
(VI) N02. tuted With one or more
When R3 is 4C03 alkyl-heteroaryl, preferably the heteroaryl (I) halogen,
is selected from the group consisting of pyridyl, pyrrolyl, 65 (II) cyano,
furanyl, thienyl, dihydrobenZofuran, indolyl, isoquinolinyl, (III) ‘CL6 alkyl,
imidaZolyl, isoXaZolyl, quinolinyl, tetrahydroquinolinyl, (IV) A)%l_6 alkyl,
US 8,114,887 B2
1 1 12
(V) C3_8 cycloalkyl, above, or a non-aromatic heterocyclic group. A non-aromatic
heterocyclic group, by itself or as part of another substituent,
(i) iC2_6 alkenyl, means a cycloalkyl group as de?ned above in Which one or
iC2-6 alkynyl, more of the ring carbon atoms is replaced With a heteroatom
(k) iCO_3 all<yl-C5_l2 heteroaryl, and (such as N, S or O). Suitable non-aromatic heterocyclic
(l) iCO_3 all<yl-C6_1O aryl, wherein said aryl moiety is groups for use in the invention include piperidinyl, piperaZi
optionally substituted With one or more nyl, morpholinyl, tetrahydrofuranyl, tetrahydrothienyl, pyr
(I) iCl-6 alkyl, rolidinyl, pyraZolidinyl, aZetidinyl, tetrahydropyranyl and
(11) 4C26 alkenyl, imidaZolidinyl. Preferred non-aromatic heterocyclic groups
(Ill) iC2_6 alkynyl, are piperidinyl, piperaZinyl, tetrahydrofuranyl, tetrahydropy
(IV) halogen, ranyl, pyrrolidinyl, morpholinyl and aZetidinyl.
(V) cyano, When a non-aromatic heterocyclic group as de?ned herein
(V 1) ‘C58 cycloalkyl, and is substituted, the substituent may be bonded to a ring carbon
(V11) N02. atom of the heterocyclic group, or on a ring heteroatom (i.e.,
In preferred embodiments of compounds of formula (III), a nitrogen, oxygen or sulfur), Which has a valence Which
XisNandZisO. permits substitution. Preferably, the sub stituent is bonded to a
As used herein, the term “alkyl,” by itself or as part of ring carbon atom. Similarly, When a non-aromatic heterocy
another substituent, means a saturated straight or branched clic group is de?ned as a substituent herein, the point of
chain hydrocarbon radical having the number of carbon attachment may be at a ring carbon atom of the heterocyclic
atoms designated (e.g., C1_ 10 alkyl means an alkyl group 20 group or on a ring heteroatom (i.e., a nitrogen, oxygen or
having from one to ten carbon atoms). Preferred alkyl groups sulfur), Which has a valence Which permits substitution. Pref
for use in the invention are C1_6 alkyl groups, having from one erably, the attachment is at a ring carbon atom.
to six carbon atoms. Exemplary alkyl groups include methyl, As used herein, the term “aryl,” by itself or as part of
ethyl, n-propyl, isopropyl, n-butyl, isobutyl, ter‘t-butyl, pen another substituent, means an aromatic cyclic hydrocarbon
tyl, hexyl, and the like. CO alkyl means a bond. 25 radical having the number of carbon atoms designated (e. g.,
As used herein, the term “alkoxy,” by itself or as part of C6_1O aryl means an aryl group having from six to ten carbons
another substituent, means the group iOi alkyl, Wherein atoms). The term “aryl” includes multiple ring systems as
alkyl is de?ned above, having the number of carbon atoms Well as single ring systems. Preferred aryl groups for use in
designated (e.g., C MO alkoxy means an alkoxy group having the invention include phenyl and naphthyl.
from one to ten carbon atoms. Preferred alkoxy groups foruse 30 The term “aryl” also includes fused cyclic hydrocarbon
in the invention are C1_6 alkoxy groups, having from one to six rings Which are partially aromatic (i.e., one of the fused rings
carbon atoms. Exemplary preferred alkoxy groups include is aromatic and the other is non-aromatic). An exemplary aryl
methoxy, ethoxy, propoxy, butoxy, sec-butoxy and pentoxy. group Which is partially aromatic is indanyl.
Especially preferred alkoxy groups are C l_3 alkoxy. The term “halo” or “halogen” includes ?uoro, chloro,
As used herein, the term “alkenyl,” by itself or as part of 35 bromo and iodo.
another substituent, means a straight or branched chain As used herein, the term “heteroaryl,” by itself or as part of
hydrocarbon radical having a single carbon-carbon double another substituent, means an aromatic cyclic group having at
bond and the number of carbon atoms designated (e.g., C2_1O least one ring heteroatom (O, N or S).). The term “heteroaryl”
alkenyl means an alkenyl group having from tWo to ten car includes multiple ring systems as Well as single ring systems.
bon atoms). Preferred alkenyl groups for use in the invention 40 Exemplary heteroaryl groups for use in the invention include
are C2_6 alkenyl groups, having from tWo to six carbon atoms. furyl, pyranyl, benZofuranyl, isobenZofuranyl, chromenyl,
Exemplary alkenyl groups include ethenyl and propenyl. thienyl, benZothiophenyl, pyrrolyl, pyraZolyl, imidaZolyl,
As used herein, the term “alkynyl,” by itself or as part of pyridyl, pyraZinyl, pyrimidinyl, pyridaZinyl, indolyl, benZ
another substituent, means a straight or branched chain imidaZolyl, quinolinyl, isoquinolinyl, tetraZolyl, indaZolyl,
hydrocarbon radical having a single carbon-carbon triple 45 napthyridinyl, triaZolyl, oxaZolyl, oxadiaZolyl, thiaZolyl,
bond and the number of carbon atoms designated (e.g., C2_1O thiadiaZolyl, isoxaZolyl, tetrahydroquinolinyl, tetrahydroiso
alkynyl means an alkynyl group having from tWo to ten car quinolinyl and dihydroindolyl.
bon atoms). Preferred alkynyl groups for use in the invention The term “heteroaryl” also includes fused aromatic cyclic
are C2_6 alkynyl groups, having from tWo to six carbon atoms. groups Which are partially aromatic (i.e., one of the fused
Exemplary alkynyl groups include ethynyl and propynyl. 50 rings is aromatic and the other is non-aromatic). Exemplary
As used herein, the term “cycloalkyl,” by itself or as part of heteroaryl groups Which are partially aromatic include tet
another substituent, means a saturated cyclic hydrocarbon rahydroquinolyl, dihydrobenZofuran and dihydroindolyl.
radical having the number of carbon atoms designated (e.g., When a heteroaryl group as de?ned herein is substituted,
C3_l2 cycloalkyl means a cycloalkyl group having from three the substituent may be bonded to a ring carbon atom of the
to tWelve carbon atoms). The term cycloalkyl as used herein 55 heteroaryl group, or on a ring heteroatom (i.e., a nitrogen,
includes mono-, bi- and tricyclic saturated carbocycles, as oxygen or sulfur), Which has a valence Which permits substi
Well as bridged and fused ring carbocycles, such as spiro tution. Preferably, the substituent is bonded to a ring carbon
fused ring systems. atom. Similarly, When a heteroaryl group is de?ned as a
Preferred cycloalkyl groups for use in the invention are substituent herein, the point of attachment may be at a ring
monocyclic C3_8 cycloalkyl groups, having from three to 60 carbon atom of the heteroaryl group, or on a ring heteroatom
eight carbon atoms. Exemplary monocyclic cycloalkyl (i.e., a nitrogen, oxygen or sulfur), Which has a valence Which
groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclo permits attachment. Preferably, the attachment is at a ring
hexyl and the like. Exemplary bridged cycloalkyl groups carbon atom.
include adamantly and norbomyl. Exemplary fused Some of the compounds of the instant invention have at
cycloalkyl groups include decahydronaphthalene. 65 least one asymmetric center. Additional asymmetric centers
As used herein, the term “carbocyclic,” by itself or as part may be present depending upon the nature of the various
of another substituent, means a cycloalkyl group as de?ned substituents on the molecule. Compounds With asymmetric
US 8,114,887 B2
13 14
centers give rise to enantiomers (optical isomers), diastere
omers (con?gurational isomers) or both, and it is intended (111')
that all of the possible enantiomers and diastereomers in Z
X, (
mixtures and as pure or partially puri?ed compounds are
included Within the scope of this invention. The present
Rl \N/ N\R2
invention is meant to encompass all such isomeric forms of
these compounds.
As used herein, the term “tautomer” refers to a compound
Which exists in an equilibrium mixture and Which can be N
isolated in either form and react through either form. The
tautomers may differ in linkage, bond, or connections | \
betWeen atoms, and the position or distribution of the atoms in
the molecule. One common form of tautomerism occurs
/\/Rl 6
When an enamine group, for example a group R2C:CRi
NHR, exists in equilibrium With its tautomeric imine form,
for example R2CH4CR:NR. In the context of this inven
tion, compounds of formula (I) may be present in the enamine and pharmaceutically acceptable salts thereof, and individual
form depicted above, or in the tautomeric imine form (1'), as enantiomers and diastereomers thereof, Wherein X', Z, R1, R2
shoWn beloW:
20 and R16 are as de?ned above.
Compounds described herein may contain one or more
double bonds, and may thus give rise to cis/trans isomers as
(1')
Well as other conformational isomers. The present invention
includes all such possible isomers as Well as mixtures of such
25 isomers.
Formulas (I) to (III) are shoWn above Without a de?nite
stereochemistry at certain positions. The present invention
includes all stereoisomers of Formulas (l) to (I11) and phar
maceutically acceptable salts thereof.
30 The independent syntheses of the enantiomerically or dias
tereomerically enriched compounds, or their chromato
graphic separations, may be achieved as knoWn in the art by
appropriate modi?cation of the methodology disclosed
and pharmaceutically acceptable salts thereof, and individual herein. Their absolute stereochemistry may be determined by
enantiomers and diastereomers thereof, Wherein X', Z, R1, R2 35 the x-ray crystallography of crystalline products or crystal
and R3 are as de?ned above. line intermediates that are derivatiZed, if necessary, With a
Additionally, compounds of formula (11) may be present in reagent containing an asymmetric center of knoWn absolute
the enamine form depicted above, or in the tautomeric imine con?guration.
form (11'), as shoWn beloW: If desired, racemic mixtures of the compounds may be
40
separated so that the individual enantiomers are isolated. The
separation can be carried out by methods Well knoWn in the
art, such as the coupling of a racemic mixture of compounds
to an enantiomerically pure compound to form a diastereo
45 meric mixture, folloWed by separation of the individual dias
tereomers by standard methods, such as fractional crystalli
Z (11')
Zation or chromatography. The coupling reaction is often the
x’% R15 formation of salts using an enantiomerically pure acid or
R1 \N/ N / / \ base. The diastereomeric derivatives may then be converted to
50 the pure enantiomers by cleavage of the added chiral residue.
The racemic mixture of the compounds can also be separated
\
directly by chromatographic methods using chiral stationary
phases, Which methods are Well knoWn in the art.
N
| Alternatively, any enantiomer of a compound may be
R3 55 obtained by stereoselective synthesis using optically pure
starting materials or reagents of knoWn con?guration by
methods Well knoWn in the art.
The compounds claimed in this invention can be prepared
according to the folloWing general procedure methods
60
(Schemes 1 and 2).
and pharmaceutically acceptable salts thereof, and individual Scheme 1 beloW depicts an Ugi four-component coupling
enantiomers and diastereomers thereof, Wherein X', Z, R1, R3 reaction betWeen a piperidone derivative, amine, isonitrile,
and R15 are as de?ned above. and cyanate, Which assembles the core structure 1-1. Further
Compounds of formula (111) may be present in the enamine 65 elaboration of 1-1 is possible, for example, removal of a
form depicted above, or in the tautomeric imine form (111'), as temporary R3 group to give 1-2, folloWed by alkylation With
shoWn beloW: a different R3 to give neW structures 1-3.
US 8,114,887 B2
16
The term “substantially pure” means that the isolated mate
rial is at least 90% pure, and preferably 95% pure, and even
more preferably 99% pure as assayed by analytical tech
niques known in the art.
The term “pharmaceutically acceptable salts” refers to
salts prepared from pharmaceutically acceptable non-toxic
bases or acids including inorganic or organic bases and inor
ganic or organic acids. The compounds of the invention may
be mono, di or tris salts, depending on the number of acid
functionalities present in the free base form of the compound.
Free bases and salts derived from inorganic bases include
aluminum, ammonium, calcium, copper, ferric, ferrous,
lithium, magnesium, manganic salts, manganous, potassium,
sodium, zinc, and the like. Particularly preferred are the
ammonium, calcium, magnesium, potassium, and sodium
salts. Salts in the solid form may exist in more than one crystal
structure, and may also be in the form of hydrates. Salts
derived from pharmaceutically acceptable organic non-toxic
bases include salts of primary, secondary, and tertiary amines,
20 substituted amines including naturally occurring substituted
amines, cyclic amines, and basic ion exchange resins, such as
arginine, betaine, caffeine, choline, N,N'-dibenzylethylene
diamine, diethylamine, 2-diethylaminoethanol, 2-dimethy
laminoethanol, ethanolamine, ethylenediamine, N-ethyl
morpholine, N-ethylpiperidine, glucamine, glucosamine,
25
histidine, hydrabamine, isopropylamine, lysine, methylglu
camine, morpholine, piperazine, piperidine, polyamine res
ins, procaine, purines, theobromine, triethylamine, trimethy
lamine, tripropylamine, tromethamine, and the like. When the
30 compound of the present invention is basic, salts may be
prepared from pharmaceutically acceptable non-toxic acids,
Alternatively, compounds of the invention where X:C including inorganic and organic acids. Such acids include
acetic, tri?uoroacetic, benzenesulfonic, benzoic, camphor
may be prepared as shown in Scheme 2, below. Strecker
sulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic,
reaction on a suitably con?gured piperidone gives nitrile 2-1
which can be hydrolyzed and esteri?ed to 2-2. Acylation to 35 hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,
mandelic, methanesulfonic, mucic, nitric, pamoic, pan
2-3 and ring closure to 2-4 followed by condensation with
tothenic, phosphoric, succinic, sulfuric, tartaric, p-toluene
amines gives compounds 2-5.
sulfonic acid, and the like. Particularly preferred are citric,
hydrobromic, hydrochloric, tri?uoroacetic, maleic, phospho
Schemel 40 ric, sulfuric, fumaric, and tartaric acids.
The present invention is directed to the use of the com
N pounds of formulas (l) to (I11) disclosed herein as inhibitors of
O \\ g EtOZC g [3-secretase enzyme activity or [3-site amyloid precursor pro
tein-cleaving enzyme (“BACE”) activity, in a patient or sub
\ R2 \ R2
45 ject such as a mammal in need of such inhibition, comprising
—> —> the administration of an effective amount of the compound.
The terms “[3-secretase enzyme,” “[3-site amyloid precursor
N N l|\l protein-cleaving enzyme,” and “BACE” are used inter
changeably in this speci?cation. In addition to humans, a
R3 R3 R3
2-1 2-2 50 variety of other mammals can be treated according to the
method of the present invention.
1
The compounds of the present invention have utility in
treating, ameliorating, controlling or reducing the risk of
Alzheimer’s disease. For example, the compounds may be
O O O
useful for the prevention of dementia of the Alzheimer’ s type,
/ EtO C Y
as well as for the treatment of early stage, intermediate stage
R1\ N\ N\ 2 N\
E% R2 0 R2 R2 or late stage dementia of the Alzheimer’s type. The com
pounds may also be useful in treating, ameliorating, control
ling or reducing the risk of diseases mediated by abnormal
11 11 11
60 cleavage of amyloid precursor protein (also referred to as
R3 R3 R3
APP), and other conditions that may be treated or prevented
2-5 2-4 2-3 by inhibition of [3-secretase. Such conditions include mild
cognitive impairment, Trisomy 21 (Down Syndrome), cere
bral amyloid angiopathy, degenerative dementia, Hereditary
Speci?c embodiments of the compounds of the invention, 65 Cerebral Hemorrhage with Amyloidosis of the Dutch-Type
and methods of making them, are described in Examples (HCHWA-D), Creutzfeld-Jakob disease, prion disorders,
(3-1)-(15-45) herein, and in Schemes 3-15. amyotrophic lateral sclerosis, progressive supranuclearpalsy,
US 8,114,887 B2
17 18
head trauma, stroke, pancreatitis, inclusion body myositis, encompass a product comprising one or more active ingredi
other peripheral amyloidoses, diabetes and atherosclerosis. ents, and an optional carrier comprising inert ingredients, as
The subject or patient to Whom the compounds of the Well as any product Which results, directly or indirectly, from
present invention is administered is generally a human being, combination, complexation or aggregation of any tWo or
male or female, in Whom inhibition of [3-secretase enZyme more of the ingredients, or from dissociation of one or more
activity is desired, but may also encompass other mammals, of the ingredients, or from other types of reactions or inter
such as dogs, cats, mice, rats, cattle, horses, sheep, rabbits, actions of one or more of the ingredients.
monkeys, chimpanZees or other apes or primates, for Which In general, pharmaceutical compositions are prepared by
inhibition of [3-secretase enZyme activity or treatment of the uniformly and intimately bringing the active ingredient into
above noted disorders is desired. association With a liquid carrier or a ?nely divided solid
The compounds of the present invention may be used in carrier or both, and then, if necessary, shaping the product
combination With one or more other drugs in the treatment of into the desired formulation. In the pharmaceutical composi
diseases or conditions for Which the compounds of the tion the active compound, Which is a compound of formulas
present invention have utility, Where the combination of the (I) to (III), is included in an amount su?icient to produce the
drugs together are safer or more effective than either drug desired effect upon the process or condition of diseases.
alone. Additionally, the compounds of the present invention Accordingly, the pharmaceutical compositions of the present
may be used in combination With one or more other drugs that invention encompass any composition made by admixing a
treat, prevent, control, ameliorate, or reduce the risk of side compound of the present invention and a pharmaceutically
effects or toxicity of the compounds of the present invention. acceptable carrier.
Such other drugs may be administered, by a route and in an 20 The carrier may take a Wide variety of forms depending on
amount commonly used therefor, contemporaneously or the form of preparation desired for administration, e.g., oral
sequentially With the compounds of the present invention. or parenteral (including intravenous). Thus, the pharmaceu
Accordingly, the pharmaceutical compositions of the present tical compositions of the present invention can be presented
invention include those that contain one or more other active as discrete units suitable for oral administration such as cap
ingredients, in addition to the compounds of the present 25 sules, cachets or tablets each containing a predetermined
invention. The combinations may be administered as part of a amount of the active ingredient. Further, the compositions can
unit dosage form combination product, or as a kit or treatment be presented as a poWder, as granules, as a solution, as a
protocol Wherein one or more additional drugs are adminis suspension in an aqueous liquid, as a non-aqueous liquid, as
tered in separate dosage forms as part of a treatment regimen. an oil-in-Water emulsion or as a Water-in-oil liquid emulsion.
Examples of combinations of the compounds of the present 30 In addition to the common dosage forms set out above, the
invention With other drugs in either unit dose or kit form compounds represented by Formulas (I) to (VII), or pharma
include combinations With anti-Alzheimer’s agents, for ceutically acceptable salts thereof, may also be administered
example other beta-secretase inhibitors or gamma-secretase by controlled release means and/or delivery devices.
inhibitors; tau phosphorylation inhibitors; M1 receptor posi Pharmaceutical compositions intended for oral use may be
tive allosteric modulators; blockers of AB oligomer forma 35 prepared according to any method knoWn to the art for the
tion; 5-HT modulators, such as PRX-03140, GSK 742467, manufacture of pharmaceutical compositions and such com
SGS-518, FK-962, SL-65.0155, SKA-333 and xaliproden; positions may contain one or more agents selected from the
p25/CDK5 inhibitors; NK1/NK3 receptor antagonists; group consisting of sWeetening agents, ?avoring agents, col
COX-2 inhibitors; HMG-CoA reductase inhibitors; NSAIDs oring agents and preserving agents in order to provide phar
including ibuprofen; vitamin E; anti-amyloid antibodies, 40 maceutically elegant and palatable preparations. Tablets may
including anti-amyloid humaniZed monoclonal antibodies; contain the active ingredient in admixture With non-toxic
anti-in?ammatory compounds such as (R)-?urbiprofen, pharmaceutically acceptable excipients Which are suitable for
nitro?urbiprofen, rosiglitaZone, ND-1251, VP-025, HT-0712 the manufacture of tablets. These excipients may be, for
and EHT-202; CB-l receptor antagonists or CB-l receptor example, inert diluents, such as calcium carbonate, sodium
inverse agonists; antibiotics such as doxycycline and 45 carbonate, lactose, calcium phosphate or sodium phosphate;
rifampin; N-methyl-D-aspartate (NMDA) receptor antago granulating and disintegrating agents, for example, corn
nists, such as memantine and neramexane; cholinesterase starch, or alginic acid; binding agents, for example starch,
inhibitors such as galantamine, rivastigmine, donepeZil, gelatin or acacia, and lubricating agents, for example magne
tacrine, phenserine, ladostigil andABT-089; groWth hormone sium stearate, stearic acid or talc. The tablets may be uncoated
secretagogues such as ibutamoren, ibutamoren mesylate, and 50 or they may be coated by knoWn techniques to delay disinte
capromorelin; histamine H3 antagonists such as ABT-834, gration and absorption in the gastrointestinal tract and
ABT 829 and GSK 189254; AMPA agonists orAMPA modu thereby provide a sustained action over a longer period.
lators, such as CX-717, LY 451395 and S-18986; PDE IV A tablet containing the composition of this invention may
inhibitors; GABAA inverse agonists; neuronal nicotinic ago be prepared by compression or molding, optionally With one
nists; selective M1 agonists; microtobubule af?nity regulat 55 or more accessory ingredients or adjuvants. Compressed tab
ing kinase (MARK) ligands; P-450 inhibitors, such as lets may be prepared by compressing, in a suitable machine,
ritonavir, or other drugs that affect receptors or enZymes that the active ingredient in a free-?owing form such as poWder or
either increase the ef?cacy, safety, convenience, or reduce granules, optionally mixed With a binder, lubricant, inert dilu
unWanted side effects or toxicity of the compounds of the ent, surface active or dispersing agent. Molded tablets may be
present invention. The foregoing list of combinations is illus 60 made by molding in a suitable machine, a mixture of the
trative only and not intended to be limiting in any Way. poWdered compound moistened With an inert liquid diluent.
The term “composition” as used herein is intended to Each tablet preferably contains from about 0.1 mg to about
encompass a product comprising speci?ed ingredients in pre 500 mg of the active ingredient and each cachet or capsule
determined amounts or proportions, as Well as any product preferably containing from about 0.1 mg to about 500 mg of
Which results, directly or indirectly, from combination of the 65 the active ingredient.
speci?ed ingredients in the speci?ed amounts. This term in Compositions for oral use may also be presented as hard
relation to pharmaceutical compositions is intended to gelatin capsules Wherein the active ingredient is mixed With