WO2008024497A2 - INHIBITORS OF 11β -HYDROXYSTEROID DEHYDROGENASE TYPE 1 - Google Patents

INHIBITORS OF 11β -HYDROXYSTEROID DEHYDROGENASE TYPE 1 Download PDF

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WO2008024497A2
WO2008024497A2 PCT/US2007/018789 US2007018789W WO2008024497A2 WO 2008024497 A2 WO2008024497 A2 WO 2008024497A2 US 2007018789 W US2007018789 W US 2007018789W WO 2008024497 A2 WO2008024497 A2 WO 2008024497A2
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adamantyl
piperidine
alkyl
indene
dihydrospiro
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PCT/US2007/018789
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French (fr)
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WO2008024497A3 (en
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David A. Claremon
Suresh B. Singh
Colin M. Tice
Yuanjie Ye
Salvacion Cacatian
Wei He
Robert Simpson
Zhenrong Xu
Wei Zhao
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Vitae Pharmaceuticals, Inc.
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Priority to EP07837345A priority Critical patent/EP2064187A2/en
Priority to US12/310,457 priority patent/US8927715B2/en
Priority to JP2009525653A priority patent/JP5420408B2/en
Priority to CA002661503A priority patent/CA2661503A1/en
Publication of WO2008024497A2 publication Critical patent/WO2008024497A2/en
Publication of WO2008024497A3 publication Critical patent/WO2008024497A3/en

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Definitions

  • the present invention relates to inhibitors of 11 ⁇ -hydroxy steroid dehydrogenase type 1 (ll ⁇ -HSDl 1 ),' pharmaceutical compositions thereof and methods of using the same.
  • Glucocorticoids such as Cortisol (hydrocortisone), axe steroid hormones that regulate fat metabolism, function and distribution, and play a role in carbohydrate, protein and fat metabolism. Glucocorticoids are also known to have physiological effects on development, neurobiology, inflammation, blood pressure, metabolism and programmed cell death. Cortisol and other corticosteroids bind both the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR), which are members of the nuclear hormone receptor superfamily and have been shown to mediate Cortisol function in vivo. These receptors directly modulate transcription via DNA-binding zinc finger domains and transcriptional activation domains.
  • Cortisol hydrocortisone
  • glucocorticoid action was attributed to three primary factors: (1) circulating levels of glucocorticoid (driven primarily by the hypothalamic-pituitary-adrenal (HPA) axis); (2) protein binding of glucocorticoids in circulation; and (3) intracellular receptor density inside target tissues.
  • HPA hypothalamic-pituitary-adrenal
  • glucocorticoid function has been identified: tissue-specific pre-receptor metabolism by glucocorticoid-activating and -inactivating enzymes.
  • 11 ⁇ - hydroxysteroid dehydrogenase (1 l ⁇ -HSD) pre-receptor control enzymes modulate activation of GR and MR by regulation of glucocorticoid hormones.
  • 1 l ⁇ -HSD 1 also known as 11 -beta-HSD type 1, l lbetaHSDl , HSDI lBl, and HSDI lL
  • 11 ⁇ -HSD2 also known as 11 -beta-HSD type 1, l lbetaHSDl , HSDI lBl, and HSDI lL
  • 1 l ⁇ -HSDl is a bi-directional oxidoreductase that regenerates active Cortisol from inactive 11 -keto forms, whereas 11 ⁇ -HSD2 is a unidirectional dehydrogenase that inactivates biologically active Cortisol by converting it into cortisone.
  • the two isoforms are expressed in a distinct tissue-specific fashion, consistent with the differences in their physiological roles.
  • 1 l ⁇ -HSDl is widely distributed in rat and human tissues; expression of the enzyme and corresponding rnRNA have been detected in human liver, adipose tissue, lung, testis, bone and ciliary epithelium.
  • increased Cortisol concentrations stimulate adipocyte differentiation and may play a role in promoting visceral obesity.
  • 1 I ⁇ -HSDI may regulate intraocular pressure and may contribute to glaucoma; some data suggests that inhibition of 1 1 ⁇ -HSDl may cause a drop in intraocular pressure in patients with intraocular hypertension (Kotelevtsev, et al., (1997), Proc. Nat'l Acad. Sci. USA 94(26): 14924-9).
  • 1 l ⁇ -HSDl catalyzes both 1 1-beta-dehydrogenation and the reverse 1 1- oxoreduction reaction
  • 1 l ⁇ -HSDl acts predominantly as a N ADPH-dependent oxoreductase in intact cells and tissues, catalyzing the formation of active Cortisol from inert cortisone (Low, et al., (1994) J. MoI. Endocrin. 13: 167-174).
  • 11 ⁇ - HSD2 expression is found mainly in mineralocorticoid target tissues such as kidney (cortex and medulla), placenta, sigmoid and rectal colon, salivary gland and colonic epithelial cell lines.
  • 11 ⁇ -HSD2 acts as an N AD-dependent dehydrogenase catalyzing the inactivation of Cortisol to cortisone (Albiston, et al., (1994) MoI. Cell. Endocrin. 105:
  • Rl 1-Rl 7 has been shown to protect the MR from glucocorticoid excess (e.g., high levels of receptor-active Cortisol) (Blum, et al., (2003) Prog. Nucl. Acid Res. MoI. Biol. 75:173-216).
  • Mutations in either the 1 l ⁇ -HSDl or the 11 ⁇ -HSD2 genes result in human pathology.
  • individuals with mutations in 1 1 ⁇ -HSD2 are deficient in this cortisol-inactivation activity and, as a result, present with a syndrome of apparent mineralocorticoid excess (also referred to as "SAME") characterized by hypertension, hypokalemia, and sodium retention (Edwards, et al., (1988) Lancet 2: 986-989; Wilson, et al., (1998) Proc. Nat'l Acad. Sci. 95: 10200-10205).
  • SAME apparent mineralocorticoid excess
  • H6PD cortisone reductase deficiency
  • PCOS polycystic ovary syndrome
  • the phenotype of Cushing's syndrome patients closely resembles that of Reaven's metabolic syndrome (also known as Syndrome X or insulin resistance syndrome), the symptoms of which include visceral obesity, glucose intolerance, insulin resistance, hypertension, type 2 diabetes and hyperlipidemia (Reaven, (1993) Ann. Rev. Med. 44, 121-131).
  • 11 ⁇ - HSDl inhibitors could be effective in combating obesity and/or other aspects of the metabolic syndrome cluster, including glucose intolerance, insulin resistance, hyperglycemia, hypertension, and/or hyperlipidemia (Kotelevstev, et al., (1997) Proc. Nat'I Acad. Sci. 94, 14924-14929; Morton et al., (2001) J. Biol. Chem. 276, 41293- 41300; Morton, et al., (2004) Diabetes 53, 931-938).
  • inhibition of 1 l ⁇ - HSDl activity may have beneficial effects on the pancreas, including the enhancement of glucose-stimulated insulin release (Billaudel & Sutter, (1979) Horm. Metab. Res. 1 1, 555-560; Ogawa, et al., (1992) J. Clin. Invest. 90, 497-504; Davani, et al., (2000) J. Biol. Chem. 275, 34841-34844).
  • Inter-individual differences in general cognitive function has been linked to variability in the long-term exposure to glucocorticoids (Lupien, et al., (1998) Nat. Neurosci. 1: 69-73) and dysregulation of the HPA axis.
  • Transgenic aP2-l 1 ⁇ -HSDl mice exhibit high arterial blood pressure and have increased sensitivity to dietary salt. Additionally, plasma angiotensinogen levels are elevated in the transgenic mice, as are angiotensin II and aldosterone. Treatment of the mice with an angiotensin II antagonist alleviates the hypertension (Masuzaki, et al., (2003) J. Clinical Invest. 112, 83-90). This suggests that hypertension may be caused or exacerbated by 1 I ⁇ -HSDI activity. Thus, ll ⁇ -HSDl inhibitors may be useful for treatment of hypertension and hypertension-related cardiovascular disorders.
  • Glucocorticoids can have adverse effects on skeletal tissues, and prolonged exposure to even moderate glucocorticoid " doses can result in osteoporosis (Cannalis, (1996) J. Clin. Endocrinol. Metab. 81, 3441-3447).
  • 1 l ⁇ -HSDl has been shown to be present in cultures of human primary osteoblasts as well as cells from adult bone (Cooper, et al., (2000) Bone 27: 375-381), and the 1 l ⁇ -HSDl inhibitor carbenoxolone has been shown to attenuate the negative effects of glucocorticoids on bone nodule formation (Bellows, et al., (1998) Bone 23 : 119-125).
  • inhibition of 1 I ⁇ -HSDI is predicted to decrease the local glucocorticoid concentration within osteoblasts and osteoclasts, thereby producing beneficial effects in various forms of bone disease, including osteoporosis.
  • novel compounds of the present invention are effective inhibitors of l l ⁇ -HSDl .
  • the present invention provides compounds of Formula I*:
  • C 5 )alkylCH ,C(0)(Co-C 3 )alkyl(C 3 -C 6 )cycloalkyl(Co-C 3 )alkylene, C(O)(C 1 -C 6 )alkylene, C(O)(C 2 -C 6 )alkenylene, S(O) 2 (Cj -C 6 )alkylene, S(O) 2 (C 2 -C 6 )alkenylene, or S(O) 2 (C 0 - C 3 )alkyl(C 3 -C 6 )cycloalkyl(Co-C 3 )alkylene, each optionally substituted with up to 4 groups, R 6 ; R 1 , K, L and R 2 are taken together to form a fused benzene or pyridine ring, which is optionally substituted with 1-3 groups independently selected from the group consisting of halogen, hydroxy, cyano, -N(R 6 ) 2 , -NR 6 C(O
  • R 2 , L, M and R 3 are taken together to form a fused benzene or pyridine ring, which is optionally substituted with 1-3 groups independently selected from the group consisting of halogen, hydroxy, cyano, -N(R 6 ) 2 , -NR 6 C(O)N(R 6 ) 2 , -NR 6 C(O)R 6 , (C 1 - C 6 )alkyl, halo(Cj-C 6 )alkyl, (Cj-C 6 )alkoxy 5 halo(C,-C 6 )alkoxy, CON(R 6 ) 2 , SO 2 N(R 6 ) 2 , -SO 2 R 6 , -NR 6 SO 2 R 6 , -NR 6 SO 2 N(R 6 ) 2 and -NR 6 SO 2 OR 6 ; or
  • R 4 , X, Y and R 5 are taken together to form a fused benzene or pyridine ring, which is optionally substituted with 1-3 groups independently selected from the group consisting of halogen, hydroxy, cyano, -N(R 6 ) 2 , -NR 6 C(O)N(R 6 ) 2 , -NR 6 C(O)R 6 , (C,- C 6 )alkyl 5 halo(C,-C 6 )alkyl, (C,-C 6 )alkoxy, halo(C r C 6 )alkoxy, CON(R 6 ) 2 , SO 2 N(R 6 ) 2 , -SO 2 R 6 , -NR 6 SO 2 R 6 , -NR 6 SO 2 N(R 6 ) 2 and -NR 6 SO 2 OR 6 ; or the group consisting of R 1 , K, L and R 2 and the group consisting of R 4 , X, Y and R 5 are each taken
  • N(R 6 ) 2 is a heterocyclyl group containing at least one nitrogen atom, preferably selected from W 1 - W 7 :
  • Q is O or NR 6 ;
  • R 7 is a saturated C7-C12 bicycloalkyl or saturated C 9 -C12 tricycloalkyl in which 1- 2 carbon atoms are optionally replaced with heteroatoms independently selected from N and O 5 and which is optionally substituted with 1-3 substituents independently selected from the group consisting of R 6 , heteroaryl, oxo-substituted heteroaryl, amino- substituted heteroaryl, heterocyclyl, oxo-substituted heterocyclyl, halogen, hydroxy, hydroxy(C,-C 6 )alkyl 5 C(NOH)NH 2 , CONHR 6 , CH 2 CONHR 6 , CON(R 6 ) 2 , CH 2 CON(R 6 ) 2 , SO 2 NHR 6 , SO 2 N(R 6 ) 2 , CO 2 R 6 , CH 2 CO 2 R 6 , SO 2 R 6 , NHCOR 6 , NR 6 COR 6 , NHCO 2 R 6 , NR 6 CO 2 R 6
  • R 1 , K 5 L and R 2 form a fused benzene or pyridine ring.
  • R 1 , K, L and R 2 form a fused benzene ring, Q is NR 6 .
  • R 1 , K, L and R 2 form a fused benzene ring
  • Q is NR 6
  • R 6 is H
  • M X and Y are all carbon
  • Z is hydrogen, Ci -C ⁇ alkyl, 2-pyridyl, 3- pyridyl, 4-pyridyl or substituted or unsubstituted phenyl
  • Q is NR 6
  • R 6 is H
  • X is C or O
  • Z is hydrogen, Ci -C ⁇ alkyl, 2-pyridyl, 3- pyrid
  • 3-pyridyl s 4-pyridyl or substituted or unsubstituted phenyl wherein if the phenyl is substituted, there are 1 or 2 substituents independently selected from the group consisting of halogen, (C]-C 6 )alkyl, (d-C 6 )alkoxy, carboxyl, cyano, loweralkylthio, carboxy-loweralkyl, nitro, -CF 3 or hydroxy.
  • R 1 , K 5 L and R 2 form a fused benzene ring
  • Q is NR 6
  • R 6 is H
  • X is C or O
  • Y is C or O
  • Z is hydrogen, (Ci-C ⁇ )alkyl 5 2-pyridyl, 3-pyridyl, 4- pyridyl or substituted or unsubstituted phenyl.
  • embodiments of Formula I* can optionally have the following provisos:
  • R 1 , K, L and R 2 form a fused benzene ring:
  • Q is O or NR 6 ;
  • R 6 is H, phenyl, (Ci-Cg)alkyl, halo(C 1 -C 8 )alkyl 5 or hydroxy(C r C s )alkyl;
  • s 1 or 2;
  • t 1 or 2; and
  • X is C, Y is C, and the M ⁇ to the fused benzene is C and the M ⁇ to the fused benzene is N or O; then R 7 must not be C7-C12 bicycloalkyl or Cp-Ci 2 tricycloalkyl;
  • R 1 , K, L and R 2 form a fused benzene ring;
  • R 4 is H;
  • R 5 is H;
  • Q is NH;
  • n 0;
  • X is C;
  • Y is C; there is an optional double bond between X and Y; then R 7 must not be substituted bicyclo[2.2.2]octane or substituted bicyclo[2.2.1 jheptane;
  • R 1 , K 5 L and R 2 form a fused benzene or pyridine ring;
  • X is N;
  • Y is C;
  • s 1 or 2;
  • t 1 or 2;
  • Q is O or NR 6 ;
  • R 6 is (Ci-C 6 )alkyl; then R 7 must not be ( ⁇ -C ⁇ bicylcoalkyl or (C 9 -Ci 2 )tricycloalkyl, wherein the bicycloalkyl and tricycloalkyl are carbocycles; and
  • provisos 1-7 can be suitably applied to all embodiments of the invention described herein. It is further understood that, depending on the embodiment of the invention, one or more of provisos 1-7 (i.e., any combination of provisos) can optionally be included in the description of any embodiment. For example, provisos 4.
  • provisos 4, 5, 6 and 7 can be individually applied to any embodiment; provisos 4 and 5, 4 and 6, or 4 and 7 can be applied in combination to any embodiment; provisos 5 and 6 or 5 and 7 can be applied in combination to any embodiment; provisos 6 and 7 can be applied in combination to any embodiment; provisos 4, 5 and 6 can be applied in combination to any embodiment; provisos 4, 5 and 7 can be applied in combination to any embodiment; provisos 4, 6 and 7 can be applied in combination to any embodiment; provisos 5, 6 and 7 can be applied in combination to any embodiment; or provisos 4, 5, 6 and 7 can be applied in combination to any embodiment.
  • A-COR 6 A-SO 2 R 6 , A-CONHSO 2 R 6 , A-CONHSO 2 N(R 6 ) 2 , A-Cs(N, alkyl, cycloalkyl, heteroaryl, aryl or arylalkyl, wherein the cycloalkyl, heteroaryl, aryl or arylalkyl groups represented by R'-R s are optionally and independently substituted with 1-3 groups independently selected from the group consisting of halogen, cyano, (Ci-C 6 )alkyl, halo(Ci-C 6 )alkyl, CONH 2 and NR 6 SO 2 R 6 , except that any one or more of R 1 - R 5 is absent where the atom to which such R 1 - R 5 group would otherwise be connected is (i) O, or (ii) an N that is connected by a double bond to an adjacent atom;
  • A is a single bond, C(R 6 ) 2 or C(R 6 ) 2 C(R 6 ) 2 ;
  • R 1 , K, L and R 2 are taken together to form a fused benzene or pyridine ring, each of which is optionally substituted with 1-3 groups independently selected from the group consisting of halogen, cyano, (Ci-C 6 )alkyl, halo(Ci-C6)atkyl, (Cj-C6)alkoxy, halo(Ci- C 6 )alkoxy, CONH 2 and NR 6 SO 2 R 6 ; or
  • R 2 , L 3 M and R 3 are taken together to form a fused benzene or pyridine ring, each of which is optionally substituted with 1 -3 groups independently selected from the group consisting of halogen, cyano, (d-C ⁇ alkyl, halo(Ci-C6)alkyl, (Ci-C6>alkoxy, halo(Ci- C 6 )alkoxy, CONH 2 and NR 6 SO 2 R 6 ; or
  • R 4 , X, Y and R 5 are taken together to form a fused benzene or pyridine ring, each of which is optionally substituted with 1-3 groups independently selected from the group consisting of halogen, cyano, (CVC ⁇ alkyl, halo(C]-C 6 )alkyl, (Ci-C ⁇ alkoxy, halo(Ci- C 6 )alkoxy, CONH 2 and NR 6 SO 2 R 6 ; or the group consisting of R 1 , K 3 L and R 2 and the group consisting of R 4 .
  • X, Y and R 5 are each taken together to form a fused benzene or pyridine ring, each of which is optionally substituted with 1-3 groups independently selected from the group consisting of halogen, cyano, (d-C 6 )alkyl 3 halo(C r C 6 )alkyl, (Ci-C 6 )alkoxy, halo(Ci-C 6 )alkoxy, CONH 2 and NR 6 SO 2 R 6 ;
  • R 6 is hydrogen, (Ci-Cio) alkyl, aryl or arylalkyl; Q is O or NR 6 ; R 7 is a saturated C 7 -Ci 2 bicycloalkyl or saturated Cg-Ci 2 tricycloalkyl in which 1- 2 carbon atoms are optionally replaced with heteroatoms independently selected from N and O, and which is optionally substituted with 1-3 substituents independently selected from the group consisting of R 6 , heteroaryl, oxo-substituted heteroaryl, amino- substituted heteroaryl, heterocyclyl, oxo-substituted heterocyclyl, halogen, hydroxy, hydroxymethyl, C(NOH)NH 2 , CONHR 6 , CH 2 CONHR 6 , CON(R 6 ) 2 , CH 2 CON(R 6 ) 2 , SO 2 NHR 6 , SO 2 N(R 6 ) 2 , CO 2 R 6 , CH 2 CO 2 R 6 , SO 2 R 6 ,
  • R 1 , K, L and R 2 form a fused benzene or pyridine ring
  • Q is NR 6
  • R 6 is H 5
  • Y is O
  • n O 5
  • X is C
  • R 4 is H and R 5 is absent
  • R 7 is not a 7- to 10- membered carbocyclic group or heterocyclic group
  • n 0 to 2
  • Z is hydrogen, (Cj-C 6 )alkyl, 2-pyridyl, 3-pyridyl, A- pyridyl or substituted or unsubstituted phenyl wherein if the phenyl is substituted, there are 1 or 2 substituents independently selected from the group consisting of halogen, (Ci- C 6 )alkyl, (Ci-C 6 )alkoxy, carboxyl, cyano, loweralkylthio, carboxyloweralkyl, nitro, -CF 3 or hydroxy.
  • R 1 if R 1 .
  • K, L and R 2 form a fused benzene ring
  • Q is NR 6
  • R 6 is H
  • M X and Y are all carbon
  • n 0 to 2.
  • Z is hydrogen, (Ci-C 6 )alkyl, 2-pyridyl, 3-pyridyl, A- pyridyl or substituted or unsubstituted phenyl wherein if the phenyl is substituted, there are 1 or 2 substituents independently selected from the group consisting of halogen, (C 1 - C ⁇ )alkyl, (Ci-C6)alkoxy, carboxyl, cyano, loweralkylthio, carboxyloweralkyl, nitro, -CF 3 or hydroxy.
  • R 1 , K, L and R 2 form a fused benzene ring
  • Q is NR 6
  • R 6 is H
  • n O
  • s 1
  • t 1 or 2
  • X is C or O
  • Y is C or O
  • Z is hydrogen, (CrC 6 )alkyl, 2-pyridyl, 3-pyridyl, 4-pyridyl or substituted or unsubstituted phenyl.
  • embodiments of Formula I can optionally have the following provisos:
  • R 1 , K, L and R 2 form a fused benzene ring;
  • Q is O or NR 6 ;
  • R 6 is H. phenyl,
  • R 1 , K, L and R 2 form a fused benzene or pyridine ring;
  • X is N;
  • Y is C;
  • n 0, 1; M, when present, is C;
  • s 1 or 2;
  • t 1 or 2;
  • Q is O or NR 6 ;
  • R 6 is (Ci-C 6 )alkyl; then R 7 5 must not be (C 7 -Ci2)bicylcoalkyl or (C 9 -Ci2)tricycloalkyl, wherein the bieycloalkyl and tricycloalkyl are carbocycles; and
  • Preferred compounds of the invention are those of any embodiment of Formulae I* or ⁇ where none of K, L, M 5 X, and Y is a basic N, and the remainder of the variables are defined above. 5 Also preferred are compounds of any embodiment of Formulae I* or I where R 1 ,
  • K, L and R 2 form a fused benzene ring, and the remainder of the variables are defined above.
  • Additionaly compounds of the invention are those of any embodiment of Formulae I* or I wherein K, L 5 M 5 X 5 and Y are individually C or O; R ! — R 5 are independently H or alkyl; and/or the bonds between K, L 5 M 5 X, and Y are all single bonds, and the remainder of the variables are defined above.
  • Q is NR 6 or O
  • R 6 is H and/or R 7 is 2-adamantyl, l-hydroxy-4-adamantyl, 1- hydroxymethyl-4-adamantyl, 1 -carbamoyl-4-adamantyl, 1 -(methylsulfonyl)-4- adamantyl, l-(aminosulfonyl)-4-adamantyl.
  • Other preferred compounds are those of Formual I* or I, wherein Q is O and/or R 7 is selected from the group consisting of 2-adamantyl, l-hydroxy-4-adamantyl, 1- hydroxymethyl-4-adamantyl, and 1 -carbamoyl-4-adamantyl, and the remainder of the variables are defined above. Also preferred compounds are those of Formula I* or I, wherein n is O 5 s is 1 , and/or t is 2, and the remainder of the variables are defined above.
  • 2-adamantyl 5-fluorospiro[indoline-3 5 4'-piperidme]-r-carboxylate 2-adamantyl 5-methylspiro[indoline-3,4'-piperidine]-l '-carboxylate; 2-adamantyl 1 -acetylspiro[indolme-3,4'-piperidine]-r-carboxylate; ⁇ ( ⁇ )-2-adamantyl 3-(2-methoxy-2-oxoethyl)-2,3-dibydrospiro[indene- 1 ,4'- piperidine]-r-carboxylate;
  • Additional compounds of the invention are those of Formula Ia:
  • R 1 - R 5 are independently hydrogen, COOR 6 , CH 2 COOR 6 , CON(R 6 ) 2 , CH 2 CON(R 6 ) 2 .
  • R 6 is hydrogen, (Ci-Cio) alkyl, aryl or arylalkyl;
  • Q is O or NR 6 ;
  • R 7 is a saturated C 7 -Cj 2 bicycloalkyl or saturated C 9 -C 12 tricycloalkyl in which 1- 2 carbon atoms are optionally replaced with heteroatoms independently selected from N and O 5 and which is optionally substituted with 1 -3 substituents independently selected from the group consisting of R 6 , heteroaryl, oxo-substituted heteroaryl.
  • NHCOR 6 NHCOR 6 , NR 6 COR 6 , NHCO 2 R 6 , NR 6 CO 2 R 6 , NHSO 2 R 6 , and NR 6 SO 2 R 6 ; or an enantiomer, diastereomer, geometrical isomer or pharmaceutically acceptable salt thereof.
  • Preferred compounds of the invention are those of Formula Ia where Q is NR 6 or O, R 6 is H and/or R 7 is 2-adamantyl, l-hydroxy-4-adamantyl, l-hydroxymethyl-4- adamantyl, 1 -carbamoyl-4-adamantyl, l-bicyclo[2.2.2]octyl, 1 -carbamoyl -4- bicyclo[2.2.2]octyl. 9-bicyclo[3.3.1]nonyl or 3-carbamoyl-9-bicyclo[3.3.1]nonyl, and the remainder of the variables are defined above.
  • Preferred compounds of the invention are those of Formula Ia where none of K, L, M, X, and Y is a basic N, and the remainder of the variables are defined above.
  • C 5 )alkylCH .C(0)(C 0 -C3)alkyl(C3-C 6 )cycloalkyl(Co-C 3 )alkylene.
  • R 6 is hydrogen, (Ci-Cio)alkyl, halo(C]-Ci 0 )alkyl, hydroxy(C,-C ]0 )alkyl 5 (R 6 ) 2 N(Ci-Cio)alkyl, aryl or arylalkyl, wherein the aryl and arylalkyl groups are optionally substituted with up to three groups independently selected from halogen, hydroxy, cyano, -N(R 6 ) 2 , -NR 6 C(O)N(R 6 ) 2 , -NR 6 C(O)R 6 , (Ci-C 6 )alkyl, halo(d-C 6 )alkyl 3 (C,-C 6 )alkoxy, halo(Ci-C 6 )alkoxy, CON(R 6 ) 2 , SO 2 N(R 6 ) 2 , -SO 2 R 6 , -NR 6 SO 2 R 6 , -NR 6 SO
  • N(R 6 ) 2 is a heterocyclyl group containing at least one nitrogen atom, preferably selected from W 1 - W 7 :
  • W 5 W 6 W 7 Q is O or NR 6 ;
  • R 7 is a saturated C 7 -Ci 2 bicycloalkyl or saturated C 9 -Ci 2 tricycloalkyl in which 1- 2 carbon atoms are optionally replaced with heteroatoms independently selected from N and O 5 and which is optionally substituted with 1 -3 substituents independently selected from the group consisting of R 6 , heteroaryl, ox o- substituted heteroaryl, amino- substituted heteroaryl, heterocyclyl, oxo-substituted heterocyclyl, halogen, hydroxy, hydroxy(C I -C 6 )alkyl, C(NOH)NH 2 , CONHR 6 , CH 2 CONHR 6 , CON(R 6 ) 2 , CH 2 CON(R 6 ) 2 , SO 2 NHR 6 , SO 2 N(R 6 ) 2 , CO 2 R 6 , CH 2 CO 2 R 6 , SO 2 R 6 , NHCOR 6 , NR 6 COR 6 , NHCO 2 R 6 , NR 6 CO
  • R 8 is independently selected from halogen, cyano, (C]-C 6 )alkyl 3 halo(d-C 6 )alkyl, (C,-C 6 )alkoxy 5 halo(C r C 6 )alkoxy, CONH 2 and NR 6 SO 2 R 6 ;
  • R 1 , R 4 and R 5 is independently H 5 COOR 6 , CH 2 COOR 6 , CON(R 6 ) 2 ,
  • R 6 is hydrogen, (Ci-C4)alkyl, aryl or arylalkyl
  • Q is O or NR 6 ; and R 7 is a saturated C7-C 12 bicycloalkyl or saturated C 9 -C 12 tricycloalkyl in which 1-
  • 2 carbon atoms are optionally replaced with heteroatoms independently selected from N and O 5 and which is optionally substituted with 1-3 substituents independently selected from the group consisting of R 6 , heteroaryl, oxo-substituted heteroaryl, amino- substituted heteroaryl.
  • heterocyclyl oxo-substituted heterocyclyl, halogen, hydroxy, hydroxymethyl, C(NOH)NH 2 , CONHR 6 , CH 2 CONHR 6 , CON(R 6 ) 2 , CH 2 CON(R 6 ) 2 , SO 2 NHR 6 , SO 2 N(R 6 ) 2 , CO 2 R 6 , CH 2 CO 2 R 6 , SO 2 R 6 , NHCOR 6 , NR 6 COR 6 , NHCO 2 R 6 , NR 6 CO 2 R 6 , NHSO 2 R 6 , and NR 6 SO 2 R 6 , or an enantiomer, diastereomer, geometrical isomer or pharmaceutically acceptable salt thereof.
  • Preferred compounds of the invention are those of Formula Ib where Q is NR 6 or O, R 6 is H and/or R 7 is 2-adamantyl, l-hydroxy-4-adamantyl, l-hydroxymethyl-4- adamantyl, 1 -carbamoyl-4-adamantyl, l-bicyclo[2.2.2]octyl, 1 -carbamoyl -4- bicyclo[2.2.2]octyl, 9-bicyclo[3.3.1]nonyl or 3-carbamoyl-9-bicyclo[3.3.1]nonyl.
  • R 1 , R 4 and R D are independently hydrogen, A-(5-tetrazolyl), A-(cycloalkyl), A-(heteroaryl), A-(hete ⁇ ocyclyl), A-(aryl), A-COOR 6 , A-CON(R 6 ) 2 , A-COR 6 , A-SO 2 R 6 , A-CONHSO 2 R 6 , A-CONHSO 2 OR 6 , A-CONHS O 2 N (R 6 ) 2 , A-CsN, alkyl, alkenyl, cycloalkyl, heteroaryl, heterocyclyl, aryl or arylalkyl, wherein the alkyl, alkenyl, cycloalkyl, heteroaryl.
  • A is a single bond, (Ci-C 6 )alkylene, (Ci-C 6 )alkenylene, (Ci-
  • C 5 )alkylCH 5 C(0)(Co-C 3 )alkyl(C 3 -C 6 )cycloalkyl(Co-C 3 )alkylene.
  • R 4 , X, Y and R 5 are taken together to form a fused benzene or pyridine ring, which is optionally substituted with 1-3 groups independently selected from the group consisting of halogen, hydroxy, cyano, -N(R 6 ) 2 , -NR 6 C(O)N(R 6 ) 2 , -NR 6 C(O)R 6 , (C]- C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C,-C 6 )alkoxy 5 halo(C 1 -C 6 )alkoxy, CON(R 6 ) 2 , SO 2 N(R 6 ) 2 , -SO 2 R 6 , -NR 6 SO 2 R 6 , -NR 6 SO 2 N(R 6 ) 2 and -NR 6 SO 2 OR 6 ; or
  • R 6 is hydrogen, (Ci-Cio)alkyl, halo(C r Cio)aIkyl, hydroxy (C] -C io)alkyl, (R 6 ) 2 N(Ci-Cio)alkyl.
  • aryl or arylalkyl wherein the aryl and arylalkyl groups are optionally substituted with up to three groups independently selected from halogen, hydroxy, cyano, -N(R 6 ) 2 , -NR 6 C(O)N(R 6 ) 2 , -NR 6 C(O)R 6 , (C,-C 6 )alkyl, halo(Ci-C 6 )alkyl, (Ci-C 6 )alkoxy, halo(C,-C 6 )alkoxy, CON(R 6 ) 2 . SO 2 N(R 6 ) 2 , -SO 2 R 6 , -NR 6 SO 2 R 6 , -NR 6 SO 2 N(R 6 ) 2 and -NR 6 SO 2 OR 6 ; or
  • N(R 6 ) 2 is a heterocyclyl group containing at least one nitrogen atom, preferably selected from W 1 - W 7 :
  • Q is O or NR 6 ;
  • R 7 is a saturated C 7 -C 12 bicycloalkyl or saturated Cp-Ci 2 tricycloalkyl in which 1- 2 carbon atoms are optionally replaced with heteroatoms independently selected from N and O, and which is optionally substituted with 1-3 substituents independently selected from the group consisting of R 6 , heteroaryl, oxo-substituted heteroaryl, amino- substituted heteroaryl. heterocyclyl, oxo-substituted heterocyclyl, halogen, hydroxy. hydroxy(Ci-C 6 )alkyl 5 C(NOH)NH 2 , CONHR 6 .
  • R 8 is independently selected from halogen, hydroxy, cyano, -N(R 6 ) 2 , -NR 6 C(O)N(R 6 ) 2 , -NR 6 C(O)R 6 , (C r C 6 )alkyl, halo(Ci-C 6 )alkyl, (C r C 6 )alkoxy, halo(C,- C 6 )alkoxy, CON(R 6 ) 2 , SO 2 N(R 6 ) 2 , -SO 2 R 6 , -NR 6 SO 2 R 6 , -NR 6 SO 2 N(R 6 ) 2 and -NR SO 2 OR 6 ; or an enantiomer, diastereomer, geometrical isomer or pharmaceutically acceptable salt thereof.
  • R 3 , R 4 and R 5 are independently H 5 COOR 6 , CH 2 COOR 6 , CON(R 6 ) 2 , CH 2 CON(R 6 ) 2 , COR 6 , SO 2 R 6 , CONHSO 2 R 6 , CH 2 CONHSO 2 R 6 , alkyl, cycloalkyl, heteroaryl, aryl or arylalkyl, wherein the cyclohexyl, heteroaryl, aryl or arylalkyl groups represented by R 3 -R 3 are optionally and independently substituted with 1-3 groups independently selected from the group consisting of halogen, cyano, (C)-C 6 )alkyl, halo(Ci-C 6 )olkyl, CONH 2 and NR 6 SO 2 R 6 , except that R 4 or R 5 is absent where the atom to which such R 4 or R 5 group would otherwise be connected is (i) O, or (ii) an N that is connected by a double bond to an adjacent atom
  • R 6 is hydrogen, (Ci-C-Oalkyl, aryl or arylalkyl;
  • Q is O or NR 6 ;
  • R 7 is a saturated C 7 -C 12 bicycloalkyl or saturated C 9 -C12 tiicycloalkyl in which 1- 2 carbon atoms are optionally replaced with heteroatoms independently selected from N and O, and which is optionally substituted with 1 -3 substituents independently selected from the group consisting of R 6 , heteroaryl, oxo- substituted heteroaryl, amino- substituted heteroaryl, heterocyclyl., oxo-substituted heterocyclyl, halogen, hydroxy, hydroxymethyl, C(NOH)NH 2 , CONHR 6 , CH 2 CONHR 6 , CON(R 6 ) 2 , CH 2 CON(R 6 ) 2; SO 2 NHR 6 , SO 2 N(R 6 ) 2 , CO 2 R 6 , CH 2 CO 2 R 6 , SO 2 R 6 , NHCOR 6 , NR 6 COR 6 , NHCO 2 R 6 , NR 6 CO 2 R 6 , NHSO 2 R 6
  • R 6 is H and/or R 7 is 2-adamantyl, 1 -hydroxy-4-adamantyl, l-hydroxymethyl-4-adamantyl or 1- carbamoyl-4-adamantyl, and the remaining variables are as defined for Formula Ic.
  • An additional embodiment of of the invention is a compound of Formula Ic':
  • R 3 - R 5 are independently hydrogen, A-(5-tetrazolyl), A-(cycloalkyl), A-(heteroaryl), A-(heterocyclyl), A-(aryl), A-COOR 6 , A-CON(R 6 ) 2 , A-COR 6 , A-SO 2 R 6 , A-CONHSO 2 R 6 , A-CONHSO 2 OR 6 ,.
  • A-CONHSO 2 N(R 6 ) 2 A-Cs(N, alkyl, alkenyL cycloalkyl, heteroaryl, heterocyclyl, aryl or arylalkyl, wherein the alkyl, alkenyl, cycloalkyl, heteroaryl, heterocyclyl, aryl, A-(cycloalkyl), A-(heteroaryl) 5
  • A-(heterocyclyl), A-(aryl) or arylalkyl groups represented by R 3 - R 5 are optionally and independently substituted with 1-3 groups independently selected from the group consisting of halogen, hydroxy, cyano, -N(R 6 ) 2 , -NR 6 C(O)N(R 6 ) 2 , -NR 6 C(O)R 6 .
  • N(R 6 ) 2 is a heterocyclyl group containing at least one nitrogen atom, preferably selected from W 1 - W 7 :
  • Q is O or NR 6 ;
  • R 7 is a saturated C 7 -Cj 2 bicycloalkyl or saturated Cg-Cn tricycloalkyl in which 1-
  • R 8 is independently selected from halogen, hydroxy, cyano, -N(R 6 ) 2 , -NR 6 C(O)N(R 6 ) 2 , -NR 6 C(O)R 6 , (C,-C 6 )alkyl, halo(Ci-C 6 )alkyl, (C r C 6 )alkoxy, halo(C,- C 6 )alkoxy, CON(R 6 ) 2 , SO 2 N(R 6 ) 2 , -SO 2 R 6 , -NR 6 SO 2 R 6 , -NR 6 SO 2 N(
  • R 6 is H and/or R 7 is 2-adamantyl, l-hydroxy-4-adamantyl, 1-hydroxym ethyl -4-adar ⁇ antyl or 1- carbamoyl-4-adamantyl, and the remaining variables are as described for Formula Ic'.
  • R 1 and R 5 are independently H, COOR 6 , CH 2 COOR 6 , CON(R 6 ) 2 , CH 2 CON(R 6 ) 2 , COR 6 , SO 2 R 6 , CONHSO 2 R 6 , CH 2 CONHSO 2 R 6 .
  • R 1 and R 5 are optionally and independently substituted with 1-3 groups independently selected from the group consisting of halogen, cyano, (Ci-C 6 )alkyl, halo(C]-C 6 )alkyl, CONH 2 and NR 6 SO 2 R 6 , except that R 1 or R 5 is absent where the atom to which such R 1 or R 5 group would otherwise be connected is (i) O, or (ii) an N that is connected by a double bond to an adjacent atom;
  • R 8 is independently selected from halogen, cyano, (Ci-C 6 )alkyl, halo(C)-C6)alkyl, (C,-C 6 )alkoxy, halo(C r C 6 )alkoxy, CONH 2 and NR 6 SO 2 R 6 ; and
  • R 7 is a saturated C 7 -Ci 2 bicycloalkyl or saturated Cg-Ci 2 tricycloalkyl in which 1- 2 carbon atoms are optionally replaced with heteroatoms independently selected from N and O, and which is optionally substituted with 1-3 substituents independently selected from the group consisting of R 6 , heteroaryl, oxo-substituted heteroaryl, amino- substituted heteroaryl, heterocyclyl, oxo-substituted heterocyclyl, halogen, hydroxy, hydroxymethyl, C(NOH)NH 2 , CONHR 6 , CH 2 CONHR 6 .
  • Preferred compounds of the invention are those of Formula Id where Q is NR 6 or O; R 6 is H; and/or R 7 is 2-adamantyl, l-hydroxy-4-adamantyl, 1 -hydroxymethyl-4- adamantyl, 1 -carbamoyl-4-adamantyl, l-bicyclo[2.2.2]octyl, 1 -carbamoyl-4- bicyclo[2.2.2]octyl, 9-bicyclo[3.3.1]nonyl or 3-carbamoyl-9-bicyclo[3.3.1]nonyl.
  • R 1 and R 5 are independently hydrogen, A-(5-tetrazolyl), A-(cycloalkyl), A-(heteroaryl), A-(heterocyclyl), A-(aryl) 5 A-COOR 6 , A-CON (R 6 ) 2 , A-COR 6 , A-SO 2 R 6 , . A-CONHSO 2 R 6 .
  • A-CONHSO 2 OR 6 A-CONHSO 2 N(R 6 ) 2 , A-C ⁇ N, alkyl, alkenyl, cycloalkyl, heteroaryl, heterocyclyl, aryl or arylalkyl, wherein the alkyl, alkenyl, cycloalkyl, heteroaryl, heterocyclyl, aryl, A-(cycloalkyl), A-(heteroaryl), A-(heterocyclyl), A-(aryl) or arylalkyl groups represented by R 1 and R 5 are optionally0 and independently substituted with 1-3 groups independently selected from the group consisting of halogen, hydroxy, cyano, -N(R 6 ) 2 , -NR 6 C(O)N(R 6 ) 2 , -NR 6 C(O)R 6 , (C,- C 6 )alkyl, halo(Ci-C 6 )alkyl, (C 1 -C 6 )
  • A is a single bond, (Cj-C6)alkylene, (C 1 -C6)alkenylene, (Ci-
  • C 5 )alkylCH ,C(0)(Co-C 3 )alkyl(C 3 -C 6 )cycloalkyl(Co-C 3 )alkylene 5 C(0)(C,-C 6 )alkylene,0 C(O)(C 2 -C 6 )alkenylene, S(O) 2 (C, -Q)alkylene, S(O) 2 (C 2 -C 6 )alkenyIene, or S(O) 2 (C 0 - C 3 )alkyl(C 3 -C 6 )cycloalkyl(Co-C 3 )alkylene, each optionally substituted with up to 4 groups, R 6 ;
  • R 6 is hydrogen, (Ci-C 10 )alkyl, halo(C r Cio)alkyl, hydroxy(Ci-Cio)alkyl, (R 6 ) 2 N(C,-C]o)alkyl, aryl or arylalkyl, wherein the aryl and arylalkyl groups are 5 optionally substituted with up to three groups independently selected from halogen, hydroxy, cyano, -N(R 6 ) 2 , -NR 6 C(O)N(R 6 ) 2 , -NR 6 C(O)R 6 , (C,-C 6 )alkyl, halo(C,-C 6 )alkyl 5 (C,-C 6 )alkoxy, halo(C,-C 6 )alkoxy, CON(R 6 ) 2 , SO 2 N(R 6 ) 2 , -SO 2 R 6 , -NR 6 SO 2 R 6 , - -NR 6 SO 2
  • N(R 6 ) 2 is a heterocyclyl group containing at least one nitrogen atom, preferably O selected from W 1 - W 7 : W 1 W 2 W 3 W 4
  • Q is O or NR 6 ;
  • R 7 is a saturated C7-C 12 bicycloalkyl or saturated C 9 -C1 2 tricycloalkyl in which 1- 2 carbon atoms are optionally replaced with heteroatoms independently selected from N and O. and which is optionally substituted with 1-3 substituents independently selected from the group consisting of R 6 , heteroaryl, oxo-substituted heteroaryl, amino- substituted heteroaryl, heterocyclyl, oxo-substituted heterocyclyl, halogen, hydroxy, hydroxy(C,-C 6 )alkyl, C(NOH)NH 2 , CONHR 6 , CH 2 CONHR 6 , CON(R 6 ) 2 , CH 2 CON(R 6 ) 2 , SO 2 NHR 6 , SO 2 N(R 6 ) 23 CO 2 R 6 , CH 2 CO 2 R 6 , SO 2 R 6 , NHCOR 6 , NR 6 COR 6 , NHCO 2 R 6 , NR 6 CO 2 R 6
  • R s is independently selected from halogen, hydroxy, cyano, -N(R 6 ) 2 , -NR 6 C(O)N(R 6 ) 2 , -NR 6 C(O)R 6 , (C,-C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C r C 6 )alkoxy, halo(C 3 - C 6 )alkoxy, CON(R 6 ) 2 , SO 2 N(R 6 ) 2 , -SO 2 R 6 , -NR 6 SO 2 R 6 , -NR 6 SO 2 N(R 6 ), and -NR 6 SO 2 OR 6 ; or an enantiomer, diastereomer, geometrical isomer or pharmaceutically acceptable salt thereof.
  • Q is O or NH; and/or R7 is 2-adamantyl, l-hydroxy-4-adamantyl, 1- (hydroxymethyl)-4-adamantyl, or l-carbamoxyl-4-adamantyl; and the rest of the variables are as described for Formula Id " ; or an enantiomer, diastereomer, geometical isomer or pharmaceutically acceptable salt thereof.
  • R 8 is independently selected from halogen, hydroxy, cyano, -N(R 6 ) 2 , -NR 6 C(O)N(R 6 ) 2 , -NR 6 C(O)R 6 , (C,-C 6 )alkyl, halo(d-C 6 )alkyl, (C,-C 6 )alkoxy, halo(C,- C 6 )alkoxy, CON(R 6 ) 2s SO 2 N(R 6 ) 2 , -SO 2 R 6 , -NR 6 SO 2 R 6 , -NR 6 SO 2 N(R 6 ) 2 and -NR 6 SOaOR 6 ; or an enantiomer, diastereomer, geometrical isomer or pharmaceutically acceptable salt thereof.
  • R 8 is independently selected from halogen, hydroxy, cyano, -N(R 6 ) 2 , -NR 6 C(O)N(R 6 ) 2 , -NR 6 C(O)R 6 , (C,-C 6 )alkyl 5 halo(C r C 6 )alkyl, (C,-C 6 )alkoxy, halo(Ci- C 6 )alkoxy, CON(R 6 ) 2 , SO 2 N(R 6 ) 2 , -SO 2 R 6 , -NR 6 SO 2 R 6 , -NR 6 SO 2 N(R 6 ) 2 and -NR 6 SO 2 OR 6 ; or an enantiomer, diastereomer, geometrical isomer or pharmaceutically acceptable salt thereof.
  • R 8 is independently selected from halogen, hydroxy, cyano, -N(R 6 )2, -NR 6 C(O)N(R 6 ) 2 , -NR 6 C(O)R 6 , (Ci-C 6 )alkyl, halo(C r C 6 )alkyl, (Ci-C 6 )alkoxy, halo(Ci- C 6 )alkoxy, CON(R 6 ) 2 , SO 2 N(R 6 ) 2 , -SO 2 R 6 , -NR 6 SO 2 R 6 , -NR 6 SO 2 N(R 6 ) 2 and -NR 6 SO 2 OR 6 ; or an enantiomer, diastereomer, geometrical isomer or pharmaceutically acceptable salt thereof.
  • R 8 is independently selected from halogen, hydroxy, cyano, -N(R 6 ) 2 , -NR 6 C(O)N(R 6 ) 2 , -NR 6 C(O)R 6 , (Ci-C 6 )alkyl, haio(Ci-C 6 )alkyl 5 (Ci-C 6 )alkoxy, halo(C r C 6 )alkoxy, CON(R 6 ) 2 , SO 2 N(R 6 ) 2 , -SO 2 R 6 , -NR 6 SO 2 R 6 , -NR 6 SO 2 N(R 6 ) 2 and -NR 6 SO 2 OR 6 ; or an enantiomer, diastereomer, geometrical isomer or pharmaceutically acceptable salt thereof.
  • X 1 is CH 2
  • X 2 is:
  • R 9 is oxo, hydroxy or thioxo
  • R 10 is H, (C 1 -C 6 )alkyl, or substituted or uhsubstituted arylalkyl
  • R 11 is independently selected from halogen, hydroxy, cyano, -N(R 6 ) 2 , -NR 6 C(O)N(R 6 ) 2 , -NR 6 C(O)R 6 , (C,-C 6 )alkyl, halo(CrC 6 )alkyl.
  • a particular embodiment of Formula Ij is a compound wherein X 2 is NR 10 and X 1 is :
  • a more particular embodiment of Formula Ij is a compound wherein X and X are defined as in the preceding paragraph, R 9 is thioxo and/or R 10 is H, methyl or 4- m ethoxybenzy 1.
  • An additional embodiment of Formula Ij is a compound, wherein X 1 is CH 2 , and X 2 is:
  • a more particular emobodiment of Formula Ij is a compound wherein X :' aanndd X ⁇ 2 are defined in the preceding paragraph, R 9 is oxo or hydroxy, and/or u is 1 and R 11 is halogen. More particularly, in one embodiment, R 1 ' is chloro.
  • a more particular emobodiment of Formula Ij is a compound wherein X 1 and X 2 are defined in the preceding paragraph, R 9 is oxo or hydroxy, and/or u is 0.
  • the present invention further provides a pharmaceutical composition comprising a disclosed 1 l ⁇ -HSDl inhibitor, including a compound of the Formulae I*, I 3 Ia, Ia', Ib, Ib', Ic 5 Ic', Id, Id', Ie, If, Ig 5 Ih, Ii or Ij and a pharmaceutically acceptable carrier.
  • the present invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising a disclosed 1 l ⁇ -HSDl inhibitor, including a compound of the Formulae I 5 Ia, Ib 5 Ic 5 or Id and a pharmaceutically acceptable carrier.
  • the present invention further provides methods of modulating 1 l ⁇ -HSDl comprising administering to a mammal in need thereof an effective amount of a disclosed 1 l ⁇ -HSDl inhibitor, including a compound of Formulae I*, I, Ia, Ia', Ib, Ib', Ic 5 Ic', Id 5 Id', Ie 5 If 5 Ig, Ih, Ii or Ij.
  • a disclosed 1 l ⁇ -HSDl inhibitor including a compound of Formulae I*, I, Ia, Ia', Ib, Ib', Ic 5 Ic', Id 5 Id', Ie 5 If 5 Ig, Ih, Ii or Ij.
  • the present invention further provides methods of modulating 11 ⁇ -HSDl by contacting 1 l ⁇ -HSDl with a disclosed 1 l ⁇ -HSDl inhibitor, including a compound of Formulae I, Ia, Ib, Ic 5 or Id.
  • the present invention further provides methods of inhibiting 11 ⁇ -HSDl comprising administering to a mammal in need thereof an effective amount of a disclosed 1 l ⁇ -HSDl inhibitor, including a compound of Formulae I, Ia, Ib, Ic or Id.
  • the present invention further provides methods of inhibiting 1 l ⁇ -HSDl comprising administering to a mammal in need thereof an effective amount of a disclosed 1 l ⁇ -HSDl inhibitor, including a compound of Formulae I*, I, Ia, Ia', Ib 5 Ib', Ic, Ic', Id, Id', Ie, If, Ig 5 Ih, Ii or Ij.
  • a disclosed 1 l ⁇ -HSDl inhibitor including a compound of Formulae I*, I, Ia, Ia', Ib 5 Ib', Ic, Ic', Id, Id', Ie, If, Ig 5 Ih, Ii or Ij.
  • the present invention further provides methods of inhibiting the conversion of cortisone to Cortisol in a cell comprising administering to a mammal in need thereof an effective amount of a compound of Formulae I, Ia, Ib 5 Ic, or Id.
  • the present invention further provides methods of inhibiting the conversion of cortisone to Cortisol in a cell comprising administering to a mammal in need thereof an effective amount of a disclosed 1 l ⁇ -HSDl inhibitor;, including a compound of Formulae I*, I, Ia, Ia', Ib, Ib', Ic, Ic', Id, Id', Ie, If, Ig, Ih, Ii or Ij.
  • the present invention further provides methods of inhibiting production of Cortisol in a cell comprising administering to a mammal in need thereof an effective amount of a disclosed 11 ⁇ -HSDl inhibitor, including a compound of Formulae I, Ia, Ib, Ic, or Id.
  • the present invention further provides methods of inhibiting production of Cortisol in a cell comprising administering to a mammal in need thereof an effective amount of a disclosed 1 l ⁇ -HSDl inhibitor, including a compound of Formulae I*, I, Ia 3 Ia', Ib, Ib', Ic, Ic', Id 3 Id', Ie 3 If 5 Ig, Ih 3 Ii or Ij.
  • a disclosed 1 l ⁇ -HSDl inhibitor including a compound of Formulae I*, I, Ia 3 Ia', Ib, Ib', Ic, Ic', Id 3 Id', Ie 3 If 5 Ig, Ih 3 Ii or Ij.
  • the present invention further provides methods of increasing insulin sensitivity comprising administering to a mammal in need thereof an effective amount of a disclosed 11 ⁇ -HSDl inhibitor, including a compound of Formulae I 3 Ia, Ib, Ic, or Id.
  • the present invention further provides methods of increasing insulin sensitivity comprising administering to a mammal in need thereof an effective amount of a disclosed 1 l ⁇ -HSDl inhibitor, including a compound of Formulae I*, I, Ia, Ia', Ib, Ib', Ic 3 Ic', Id, Id', Ie, If, Ig 3 Ih, Ii or Ij.
  • the present invention further provides methods of treating diseases associated with activity or expression of 11 ⁇ -HSDl comprising administering to a mammal in need thereof an effective amount of a disclosed 1 l ⁇ -HSDl inhibitor, including a compound of Formulae I, Ia, Ib, Ic 3 or Id.
  • the present invention further provides methods of treating diseases associated with activity or expression of 11 ⁇ -HSDl comprising administering to a mammal in need thereof an effective amount of a disclosed 1 l ⁇ -HSDl inhibitor, including a compound of Formulae I*, I 3 Ia, Ia', Ib, Ib', Ic, Ic', Id, Id', Ie, If, Ig 3 Ih, Ii or Ij.
  • a disclosed 1 l ⁇ -HSDl inhibitor including a compound of Formulae I*, I 3 Ia, Ia', Ib, Ib', Ic, Ic', Id, Id', Ie, If, Ig 3 Ih, Ii or Ij.
  • a disclosed 11 ⁇ -HSDl inhibitor including a compound of Formulae I*, I 3 Ia, Ia', Ib 3 Ib', Ic 3 Ic', Id, Id% Ie 3 If 3 Ig, Ih, Ii or Ij or a pharmaceutically acceptable salt thereof for the manufacture of a medicament, wherein the values for the variables are as described above for the pharmaceutical composition of the invention.
  • the medicament is for treating a disease or disorder related to the activity or expression of 1 l ⁇ -HSDl , inhibiting the conversion of cortisone to Cortisol in a cell, inhibiting production of Cortisol in a cell, increasing insulin sensitivity, modulating 11 ⁇ -HSDl, and/or inhibiting 1 l ⁇ -HSDl.
  • a disclosed 1 l ⁇ -HSDl inhibitor including a compound of Formulae I*, I, Ia, Ia', Ib, Ib', Ic, Ic', Id. Id', Ie 3 If 3 Ig, Ih, Ii or Ij or a pharmaceutically acceptable salt thereof for therapy, such as treating a disease or disorder related to the activity or expression of 11 ⁇ -HSDl, inhibiting the conversion of cortisone to Cortisol in a cell, inhibiting production of Cortisol in a cell, increasing insulin sensitivity, modulating 1 l ⁇ -HSDl, and/or inhibiting 1 l ⁇ -HSDl. Values for the variables of the Formulae are as described above.
  • a disclosed 1 l ⁇ -HSDl inhibitor including a compound of Formulae I*, I, Ia 5 Ia', Ib, Ib', Ic, Ic', Id, Id', Ie, If, Ig, Ih, Ii or Ij or a pharmaceutically acceptable.salt thereof for treating a disease or disorder related to the activity or expression of 1 l ⁇ -HSDl, inhibiting the conversion of cortisone to Cortisol in a cell, inhibiting production of Cortisol in a cell, increasing insulin sensitivity, modulating 1 l ⁇ -HSDl, and/or inhibiting 1 l ⁇ -HSDl .
  • Values for the variables of the Formuale are as described above.
  • variable e.g., aryl, heterocyclyl, R 1 , R 2 , etc.
  • alkyl means a straight or branched hydrocarbon radical having 1-10 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-buryl, sec- butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like.
  • loweralkyl means a C 1 -C 7 straight or branched alkyl group.
  • Alkylene means a saturated aliphatic straight-chain divalent hydrocarbon radical having the specified number of carbon atoms, e.g., -(CHa) x - wherein x is a positive integer such as 1-10, preferably 1-6.
  • (Ci-C 6 )alkylene means a radical having from 1-6 carbon atoms in a linear or branched arrangement, with optional unsaturation or optional substitution.
  • cycloalkyl means a saturated hydrocarbon ring having 3-8 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
  • bicycloalkyF means two saturated hydrocarbon rings having a total of 7-12 carbon atoms which are joined by 1,1-fusion, 1,2-fusion or l,n-fusion to give spirocyclic ring systems, fused ring systems and bridged ring systems respectively.
  • Spirocyclic ring systems include, for example, spiro[2.4]heptane, spiro[2.5]octane, spiro[4.4]nonane, spiro[4.5]decane, spiro[5.5]undecane and the like.
  • Fused ring systems include, for example, bicyclo[4.1.0]heptane, octahydro-lH-indene, decahydronaphthalene and the like.
  • Bridged ring systems include for example, bicyclo[3.3.1]nonane, bicyclo[2.2.2]octane, bicyclo[2.2.1]heptane and the like.
  • tricycloalkyl means three saturated hydrocarbon ring having a total of 9-12 carbon atoms which are joined by any combination of 1,1-fusion, 1,2-fusion or l,n- fusion and includes, for example, adamantyl, noradamantyl and the like.
  • alkoxy and alkylthio are O-alkyl or S-alkyl, respectively, of 1-6 carbon atoms as defined above for “alkyl.”
  • aryl means an aromatic radical which is a phenyl group, a phenylalkyl group, a phenyl group substituted with 1-4 substituents selected from alkyl as defined above, alkoxy as defined above, alkylthio as defined above, halogen, trifluoromethyl, dialkylamino as defined above for alkyl, nitro. cyano, and N,N-dialkyl-substituted amido as defined above for alkyl.
  • heteroaryl means a 5- and 6- membered heteroaromatic radical which may optionally be fused to a ring containing 1-4 heteroatoms selected from N, O, and S and includes, for example, a heteroaromatic radical which is 2- or 3-thienyl, 2- or 3- furanyl, 2- or 3- pyrrolyl.
  • heterocyclyl means a 4-, 5-, 6- and 7-membered saturated or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O, and S 3 and include pyrrolidine, piperidine.
  • arylalkyl means an aromatic radical attached to an alkyl radical wherein aryl and alkyl are as defined above, for example, benzyl, phenethyl, and the like.
  • adamantyl means an adamantane moiety bonded to another atom via the 1- or 2- position of adamantane.
  • a “carbocyclic group” comprises at least one ring formed entirely by carbon- carbon bonds. Such a group generally has from 1 to 3 fused or pendant rings, preferably one ring or two fused rings. Typically, each ring contains from 3 to 10 ring members, preferably from 5 to 8 ring members. Unless otherwise specified, such a ring may be aromatic or non-aromatic.
  • carbocyclic groups are cycloalkyl groups (e.g., cyclopentane and cyclohexane), cycloalkenes and cycloalkynes, as well as aromatic groups such as phenyl, benzyl, naphthyl, phenoxyl, benzoxyl and phenylethanonyl. Carbon atoms present within a carbocyclic group may.
  • ring substituents such as hydrogen, a halogen, cyano, nitro, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 1 -C 8 alkoxy, C)-C 8 alkylthio, hydroxy, amino, mono or di(C]-C8)alkylamino, (C3-C 7 )cycloalkyl(Co-C3)alkyL halo(C]-Cs)alkyl, halo(Ci-C 8 )alkoxy, Ci-C 8 alkanoyl, Ci-C 8 alkoxycarbonyl, -COOH, -CONH 2 , mono- or di-(Ci-Cs)alkylcarboxamido, -SO2NH 2 , and mono or di(C]-Cg)alkylsulfonamido.
  • ring substituents such as hydrogen, a halogen, cyano, nitro,
  • a “heterocyclic group” comprises at least one ring in which at least one ring atom is a heteroatom (i.e., N, O or S), and the remainder of the ring atoms are carbon.
  • a heterocyclic group comprises 1 -4 heteroatoms; within certain embodiments 1 or 2 heteroatoms is preferred.
  • a heterocyclic group generally has from 1 to 3 fused or pendant rings, preferably one ring or two fused rings. Typically, each ring contains from 3 to 10 ring members, preferably from 5 to 8 ring members, and may be optionally substituted with from 1 to 5 substituents such as halogen, cyano, nitro, Ci-C 8 alkyl, C 2 - Cg alkenyl.
  • a heterocyclic group may be aromatic or nonaromatic. As with a carbocyclic group, atoms within a heterocyclic ring may be further linked to a variety of ring substituents.
  • a heterocyclic ring may be attached to a pendant group at any heteroatom or carbon atom that results in a stable structure.
  • the heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable.
  • a nitrogen in the heterocycle may optionally be quaternized.
  • the total number of S and O atoms in the heterocycle exceeds I 5 then these heteroatoms are not adjacent to one another. More preferably, the total number of S and O atoms in the heterocycle is not more than 1.
  • heterocyclic groups include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothio-furanyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, dithiaz ⁇ nyl, dihydrofurotetrahydrofuran, fiiranyl, furazanyl, imidazolidinyl, imidazoli ⁇ yl, imidazolyl, indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, iso
  • heterocyclic groups include, for example, pyridyl, pyrimidinyl (e.g., pyrimidin-2-yl), pyridinyl (pyridin-2-yl, pyridin-3-yl and pyridin-4-yl), morpholinyl (e.g., morpholin-4-yl), piperidinyl (e.g., piperidin-1-yl), pyrrolidinyl (e.g., pyrrolidin-1- yl), tetrazolyl, triazinyl, thienyl, coumarinyl.
  • pyridyl e.g., pyrimidin-2-yl
  • pyridinyl pyridin-2-yl
  • morpholinyl e.g., morpholin-4-yl
  • piperidinyl e.g., piperidin-1-yl
  • halogen means fluorine, chlorine, iodine or bromine.
  • basic nitrogen refers to a nitrogen atom that is >50% protonated in aqueous solution at pH 7 and includes, for example, the nitrogen atoms dialkylamines and trialkylamines.
  • the compounds of the invention may be present in the form of pharmaceutically acceptable salts.
  • the salts of the compounds of the invention refer to non-toxic "pharmaceutically acceptable salts.”
  • Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/cationic salts.
  • Pharmaceutically acceptable acidic/anionic salts include, the acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide; calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate, glutamate, glycoUylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate f maleate, mandelate, mesylate, methylsulfate.
  • the compounds of the invention include pharmaceutically acceptable anionic salt forms, wherein the anionic salts include the acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate.
  • the anionic salts include the acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glycept
  • iodide isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate/diphospate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate. tosylate, and triethiodide salts.
  • solvates or hydrates of the compound or its pharmaceutically acceptable salts are also included.
  • Solvates refer to crystalline forms wherein solvent molecules are incorporated into the crystal lattice during crystallization.
  • Solvate may include water or nonaqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and EtOAc.
  • Solvates, wherein water is the solvent molecule incorporated into the crystal lattice are typically referred to as "hydrates". Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water.
  • a disclosed compound or its pharmaceutically acceptable salt When a disclosed compound or its pharmaceutically acceptable salt is named or depicted by structure, it is to be understood that the compound, including solvates thereof, may exist in crystalline forms, non-crystalline forms or a mixture thereof.
  • the compound or its pharmaceutically acceptable salts or solvates may also exhibit polymorphism (i.e. the capacity to occur in different crystalline forms). These different crystalline forms are typically known as "polymorphs.”
  • polymorphs typically known as “polymorphs.”
  • the disclosed compound and its pharmaceutically acceptable salts, solvates or hydrates also include all polymorphs thereof. Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state.
  • Polymorphs may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification.
  • different polymorphs may be produced, for example, by changing or adjusting the conditions used in solidifying the compound. For example, changes in temperature, pressure, or solvent may result in different polymorphs.
  • one polymorph may spontaneously convert to another polymorph under certain conditions.
  • the invention also includes various isomers and mixtures thereof.
  • “Isomer” refers to compounds that have the same composition and molecular weight but differ in physical and/or chemical properties. The structural difference may be in constitution (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers).
  • Stereoisomers are compounds that differ only in their spatial arrangement. Enantiomers are pairs of stereoisomers whose mirror images are not superimposable, most commonly because they contain an asymmetrically substituted carbon atom that acts as a chiral center. "Enantiomer” means one of a pair of molecules that are mirror images of each other and are not superimposable. Diastereomers are stereoisomers that are not related as mirror images, most commonly because they contain two or more asymmetrically substituted carbon atoms.
  • Racemate or “racemic mixture” means a compound of equimolar quantities of two enantiomers, wherein such mixtures exhibit no optical activity; i.e., they do not rotate the plane of polarized light.
  • “Geometric isomer” means isomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a cycloalkyl ring, or to a bridged bicyclic system. Atoms (other than H) on each side of a carbon-carbon double bond may be in an E (substituents are on opposite sides of the carbon-carbon double bond) or Z (substituents are oriented on the same side) configuration.
  • the compounds of the invention may be prepared as individual isomers by either isomer-specific synthesis or resolved from an isomeric mixture.
  • Conventional resolution techniques include forming the salt of a free base of each isomer of an isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each isomer of an isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each of the isomers of an isomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving an isomeric mixture of either a starting material or a final product using various well known chromatographic methods.
  • a pharmaceutical composition of the invention may, alternatively or in addition to a compound of Formulae I*.
  • I 3 Ia, Ia', Ib, Ib', Ic, Ic', Id, Id'. Ie 5 If.
  • Ig, Ih 5 Ii or Ij comprise a pharmaceutically acceptable salt of a compound of Formulae 1*, I 5 Ia, Ia% Ib, Ib', Ic, Ic' , Id 3 Id', Ie 3 If 3 Ig 3 Ih 3 Ii or Ij 3 or a prodrug or pharmaceutically active metabolite of such a compound or salt and one or more pharmaceutically acceptable carriers therefor.
  • Prodrug means a pharmaceutically acceptable form of an effective derivative of a compound (or a salt thereof) of the invention, wherein the prodrug may be: 1) a relatively active precursor which converts in vivo to a compound of the invention; 2) a relatively inactive precursor which converts in vivo to a compound of the invention; or 3) a relatively less active component of the compound that contributes to therapeutic activity after becoming available in vivo (i.e., as a metabolite).
  • Methodabolite means a pharmaceutically acceptable form of a metabolic derivative of a compound (or a salt thereof) of the invention, wherein the derivative is an active compound that contributes to therapeutic activity after becoming available in vivo.
  • Effective amount means that amount of active compound agent that elicits the desired biological response in a subject. Such response includes alleviation of the symptoms of the disease or disorder being treated.
  • the effective amount of a compound of the invention in such a therapeutic method is from about 10 mg/kg/day to about 0.01 mg/kg/day, preferably from about 0.5 mg/kg/day to 5 mg/kg/day.
  • I ⁇ -HSDI Inhibiting 1 I ⁇ -HSDI means to decrease the activity of the 1 l ⁇ -HSDl enzyme.
  • Modulating 11 ⁇ -HSD 1 means to impact the activity of the 11 ⁇ -HSD 1 enzyme by altering its natural activity. Modulation can be analogous to inhibition when a disease or disorder relating to the activity 11 ⁇ -HSD 1 would be effectively treated by suppressing the activity of the enzyme.
  • “Pharmaceutically acceptable carrier” means compounds and compositions that are of sufficient purity and quality for use in the formulation of a composition of the invention and that, when appropriately administered to an animal or human, do not produce an adverse reaction.
  • Treatment' * or “treating”, as used herein, refers to partially or totally inhibiting, delaying, or reducing the severity of the disease or disorder related to 11 ⁇ -HSD 1.
  • treatment and “treating” also encompass the prophylactic administration of a compound of the invention to a subject susceptible to a disease or disorder related to the activity or expression of 1 l ⁇ -HSDl in an effort to reduce the likelihood of a subject developing the disease or disorder, or slowing or preventing progression of the disease.
  • Prophylactic treatment includes suppression (partially or completely) of the disease or disorder, and further includes reducing the severity of the disease or disorder, if onset occurs.
  • Prophylactic treatment is particularly advantageous for administration to mammals at risk for developing a disease or disorder related to 11 ⁇ -HSDl .
  • the compounds of the present invention can be prepared and administered in a wide variety of oral and parenteral. dosage forms.
  • the compounds of the present invention can be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally. Additionally, the compounds of the present invention can be administered intranasally or transdermally.
  • dosage forms may comprise as the active ingredient, either compounds or a corresponding pharmaceutically acceptable salt of a compound of the present invention.
  • pharmaceutically acceptable carriers can either be solid or liquid.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersable granules.
  • a solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier is a finely divided solid which is in a mixture with the finely divided active ingredient.
  • the active ingredient is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain from about one to about seventy percent of the active ingredient.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcelluose, a low melting wax, cocoa butter, and the like. Tablets, powders, cachets, lozenges, fast-melt strips, capsules and pills can be used as solid dosage forms containing the active ingredient suitable for oral administration.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter
  • the active ingredient is dispersed homogeneously therein, as by stirring.
  • the molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
  • Liquid form preparations include solutions, suspensions, retention enemas, and emulsions, for example, water or water propylene glycol solutions.
  • liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
  • Aqueous solutions suitable for oral administration can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, stabilizing , and thickening agents as desired.
  • Aqueous suspensions for oral administration can be prepared by dispersing the finely divided active ingredient in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethyl cellulose, and other well-known suspending agents.
  • the pharmaceutical composition is preferably in unit dosage form.
  • the composition is subdivided into unit doses containing appropriate quantities of the active ingredient.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of, for example, tablets, powders, and capsules in vials or ampules.
  • the unit dosage form can be a tablet, cachet, capsule, or lozenge itself, or it can be the appropriate amount of any of these in packaged form.
  • the quantity of active ingredient in a unit dose preparation may be varied or adjusted from about 0.1 mg to about 1000.0 mg, preferably from about 0.1 mg to about 100 mg.
  • the dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill in the art.
  • the pharmaceutical composition may contain, if desired, other compatible therapeutic agents.
  • the active ingredient is preferably administered orally in a solid dosage form as disclosed above in an amount of about 0.1 mg to about 100 mg per daily dose where the dose is administered once or more than once daily.
  • the compounds of the invention are useful for ameliorating or treating disorders or diseases in which decreasing the level of Cortisol is effective in treating a disease state.
  • the compounds of the invention can be used in the treatment or prevention of diabetes mellitus, obesity, metabolic syndrome, insulin resistance, cardiovascular disease, dyslipidemia, atherosclerosis, lipodystrophy, osteoporosis, glaucoma, Cushing's syndrome, depression, anxiety and Alzheimer's disease, cognitive decline (including age-related cognitive decline), polycystic ovarian syndrome and infertility.
  • . compounds modulate the function of B and T cells of the immune system.
  • a pharmaceutical composition of the invention may, alternatively or in addition to a compound of Formulae I*, I, Ia, Ia', Ib ? Ib', Ic, Ic', Id, Id', Ie, If, Ig, Ih, Ii or Ij, comprise a pharmaceutically acceptable salt of a compound of Formulae I*, I, Ia, Ia', Ib, Ib', Ic 5 Ic', Id, Id', Ie, If, Ig, Ih, Ii or Ij, or a prodrug or pharmaceutically active metabolite of such a compound or salt and one or more pharmaceutically acceptable carriers therefor.
  • compositions of the invention are 1 l ⁇ -HSDl inhibitors.
  • Said compositions contain compounds having a mean inhibition constant (IC 5 o) against 11 ⁇ - HSDl of between about 1,000 nM to about 0.001 nM; preferably between about 50 nM to about 0.001 nM; and more preferably between about 5 nM to about 0.01 nM.
  • the invention includes a therapeutic method for treating or ameliorating an 1 l ⁇ -HSDl mediated disorder in a subject in need thereof comprising administering to a subject in need thereof an effective amount of a compound of Formulae I*, I, Ia, Ia', Ib, Ib', Ic, Ic', Id, Id', Ie, If, Ig, Ih, Ii or Ij, or the enantiomers, diastereomers, or salts thereof or composition thereof.
  • the compounds of the invention are useful for ameliorating or treating disorders or diseases in which decreasing the level of Cortisol is effective in treating a disease state.
  • the compounds of the invention can be used in the treatment or prevention of diabetes mellitus, obesity, symptoms of metabolic syndrome, glucose intolerance, hyperglycemica, hypertension, hyperlipidemia, insulin resistance, cardiovascular disease, dyslipidemia, atherosclerosis, lipodystrophy, osteoporosis, glaucoma, Cushing's syndrome, Addison's Disease, visceral fat obesity associated with glucocorticoid therapy, depression, anxiety, Alzheimer's disease, dementia, cognitive decline (including age-related cognitive decline), polycystic ovarian syndrome and infertility.
  • the compounds modulate the function of B and T cells of the immune system and can therefore be used to treat diseases such as tuberculosis, leprosy and psoriasis. They can also be used to promote wound healing, particularly in diabetic patients.
  • Additional diseases or disorders that are related to 11 ⁇ -HSDl activity include those selected from the group consisting of lipid disorders, hypretriglyceridemia, hypercholesterolemia, low HDL levels, high LDL levels, vascular restenosis, pancreatitis, abdominal obesity, neurodegenerative disease, retinopathy, nephropathy, neuropathy, diabetes, coronary heart disease, stroke, peripheral vascular disease, Gushing' s syndrome, hyperinsulinemia, viral diseases, and Syndrome X.
  • An embodiment of the invention includes administering an ll ⁇ -HSDl inhibiting compound of Formula I or pharmaceutical composition thereof in a combination therapy with one or more additional agents for the treatment of diabetes, dyslipidemia, cardiovascular disease, hypertension, obesity, cancer or glaucoma.
  • Agents for the treatment of diabetes include insulins, such as Humulin® (Eli Lilly), Lantus® (Sanofi Aventis), Novolin (Novo Nordisk), and Exubera® (Pfizer); PPAR gamma agonists, such as Avandia® (rosiglitazone maleate, GSK) and Actos® (pioglitazone hydrochloride, Takeda/EIi Lilly); sulfonylureas, such as Amaryl® (glimepiride, Sanofi Aventis), Diabeta® (glyburide, Sanofi Aventis), Micronase®/Glynase® (glyburide, Pfizer), and Glu
  • Agents for the treatment of dyslipidemia and cardiovascular disease include statins, fibrates and ezetim ⁇ be.
  • Agents for the treatment of hypertension include ⁇ - blockers, ⁇ -blockers, calcium channel blockers, diuretics, angiotensin converting enzyme (ACE) inhibitors, dual ACE and neutral endopeptidase (NEP) inhibitors, angiotensin- receptor blockers (ARBs), aldosterone synthase inhibitor, aldosterone-receptor antagonists, or endothelin receptor antagonist.
  • Agents for the treatment of obesity include orlistat, phentermine, sibutramine and rimonabant.
  • An embodiment of the invention includes administering an ll ⁇ -HSDl inhibiting compound of Formula I or composition thereof in a combination therapy with one or more other ll ⁇ -HSDl inhibitors (whether such inhibitors are also compounds of Formula I or are compounds of a different class/genus), or with combination products, such as Avandamet® (metformin HCl and rosiglitazone maleate. GSK); Avandaryl® (glimepiride and rosiglitazone maleate, GSK); Metaglip® (glipizide and metformin HCl, Bristol Myers Squibb); Janumet® (sitagliptin and metformin. Merck)and Glucovance® (glyburide and metformin HCl, Bristol Myers Squibb).
  • Avandamet® metalformin HCl and rosiglitazone maleate. GSK
  • Avandaryl® glimepiride and rosiglitazone maleate, GSK
  • O is prepared by reaction of an amine of formula II with a chloroformate of formula III in the presence of an organic or inorganic base, for example N.N-diisopropylethylamine or K 2 CO 3 , in an inert solvent such as CH 2 Cl 2 , MeCN or THF at -20 0 C to 80 0 C, preferably O 0 C to 25 0 C for between 0.5 h and 24 h.
  • an organic or inorganic base for example N.N-diisopropylethylamine or K 2 CO 3
  • an inert solvent such as CH 2 Cl 2 , MeCN or THF at -20 0 C to 80 0 C, preferably O 0 C to 25 0 C for between 0.5 h and 24 h.
  • spirocyclic amines of Formula II can be prepared by previously described routes or can be purchased.
  • Ethyl 2-(7-bromospiro[indene-l 5 4'-piperidine]-3(2H)-ylidene)acetate was purchased from WuXi Pharmatech (Shanghai, China):
  • Example 19 can be prepared from 8-benzy]-2-oxa-8-azaspiro[4.5]decane-l,3-dione as disclosed in Example 19 (Steps A- G) of US Published Patent Application 2003/055244, which is hereby incorporated by reference. This compound was purchased from WuXi Pharmatech (Shanghai, China).
  • Example 1 can be prepared by deprotection of r-(tert-butoxycarbonyl)-2,3-dihydrospiro [indene- 1 ,4'-piperidine]-3-carboxylic acid which can be prepared from tert-butyl 3-oxo-2.3- dihydrospiro[indene-l,4'-piperidine]-r-carboxylate as disclosed in Example 1 (Steps A — D) of US Patent No. 5,965,565, which is hereby incorporated by reference. This compound was purchased from WuXi Pharmatech (Shanghai. China).
  • Example A3 (Steps (a) and (b)) of US Published Patent Application 2003/0139393, which is hereby incorporated by reference.
  • Example 3 can be prepared as disclosed in Example 3 (Steps A - C) of WO 2005/061512 Al 5 which is hereby incorporated by reference.
  • Example 12 can be prepared as disclosed in Example 12 (Step A) of US Patent No. 5,536,716, which is hereby incorporated by reference.
  • chloroformates of formula III are prepared by reaction of alcohols of formula IV with phosgene or triphosgene in an inert solvent such as toluene, CH 2 CI2 or THF in the presence of a base such as pyridine at -20 0 C to 8O 0 C 5 preferably 0 0 C to 25°C for between 0.5 h and 24 h.
  • Isocyanates of formula V are prepared by reaction of amines of formula VI with phosgene or triphosgene in, for example, a mixture of CH 2 Cl 2 and satd aq NaHCC> 3 at -10 0 C to80°C, preferably 0 0 C to 25°C for between 0.5 h and 24 h.
  • LG is a leaving group such as halide, aryloxide or azole, for example chloride, p- nitrophenoxide or imidazolide
  • LG is a leaving group such as such as halide, aryloxide or azole, for example chloride, p-nitrophenoxide or imidazolide
  • LG is a leaving group such as such as halide, aryloxide or azole, for example chloride, p-nitrophenoxide or imidazolide
  • a compound of Formula I or I* is prepared by derivatizing compound of Formula I or I* that has a reactive site such as an amine or carboxylic acid.
  • R 4 ACOoH
  • R 6 alkyl, alkylaryl
  • R 4 ACO 2
  • R 4 ACONHp
  • R 4 ACN
  • R 4 ACO 1 H
  • R 4 ACON(R 6 )SO,R 6 i) reaction of a compound of Formula I or I* wherein R 7 is a bi- or tricycloalkyl group bearing a CO 2 Me substituent with an alkali metal hydroxide in a mixture of water and a lower alkanol or THF at 0 0 C to 50°C between 3 h and 24 h to give a compound of Formula I or I* wherein R 7 is a bi- or tricycloalkyl group bearing a CO 2 H substituent:
  • R 7 a bi- or tricycloalkyl group
  • R 7 a bi- or tricycloalkyl group substituted with CO 2 Me substituted with CO 2 H j) reaction of a compound of Formula I or I* wherein R 7 is a bi- or tricycloalkyl group bearing a CO 2 Me substituent with a nucleophilic species such as iodide or a thiol anion to give a compound of Formula I or I* wherein R 7 is a bi- or tricycloalkyl group bearing a CO 2 H substituent:
  • R 7 a bi- or tricycloalkyl group
  • R 7 a b ⁇ - or tricycloalkyl group substituted with CO 2 Me substituted with CO 2 H k) a two step reaction of a compound of Formula I or I* wherein R 7 is a bi- or tricycloalkyl group bearing a CO 2 H- substituent with thionyl chloride or oxalyl chloride in CH 2 Cl 2 at -20 0 C to 80 0 C for between 0.5 h and 24 h to convert the CO 2 H substituent to an acid chloride substituent followed by treatment with at least one equivalent of ammonia in an inert solvent such as CH 2 Cl 2 or THF, optionally in the presence of a base such as triethylamine or pyridine, at -2O 0 C to 40 0 C to give a compound of Formula I or I* wherein R 7 is a bi- or tricycloalkyl group bearing a CONH 2 substituent:
  • R 7 a bi- or tricycloalkyl group
  • R 7 a bi- or tricycloalkyl group substituted with CO 2 H substituted with CONH 2
  • reaction of a compound of Formula I or I* wherein R 7 is a bi- or tricycloalkyl group bearing a CO 2 Me substituent with an alkali borohydride in THF at -20 0 C to 50 0 C for between 1 h and 24 h to give a compound of Formula I or I* wherein R 7 is a bi- or tricycloalkyl group bearing a CH 2 OH substituent:
  • R 7 a bi- or tricycloalkyl group
  • R a bi- or tricycloalkyl group substituted with CO 2 Me substituted with CH 2 OH ⁇
  • prep HPLC refers to preparative reverse phase HPLC on a C- 18 column eluted with a water/acetonitrile gradient containing 0.01 % TFA run on a Gilson 215 system.
  • Step 4 A mixture of l-benzoylo-benzyl-piperidine-S-carboxylic acid (6.71 g 5 20.7 mmol) and thionyl chloride (2.70 g 5 22.77 mmol) in dry CH 2 Cl 2 (25 mL) was heated to reflux for 30 min. The resulting solution was concentrated in vacuum to give a light brown oil. A solution of this oil in dry CH 2 C1 2 (25 mL) was added dropwise to a mixture OfAlCl 3 (3.59 g, 26.91 mmol) in CH 2 Cl 2 (10 mL) at 0 0 C. The mixture was stirred for 15 min at 0 0 C and then heated to reflux for 45 min.
  • Step 1 To a solution of tert-butyl 7-bromo-3-(2-ethoxy-2-oxoethyl)-2,3- dihydrospiro[indene-l,4'-pi ⁇ eridi ⁇ e]-r-carboxylate (500 mg, 1.11 mmol) was added LiHMDS (2.4 mL, 1 M 5 2.4 mmol) followed by HMPA at -1O 0 C under N 2 . The mixture was stirred for 1 h and CH 3 I (142 mg, 8.8 mmol) was added to the solution. After addition, the mixture was stirred overnight.
  • 2-methylspiro[isoindoline-1.4'-piperidine]-3-thione was prepared following procedures analogous to those described in Preparation 10 using 2-iodobenzoyl chloride in place of 3-chloro-2-iodobenzoyl chloride and methylamine in place of 4- methoxybenzylamine in Step 1.
  • Step 1 Tert-butyl 2-(4-methoxybenzyl)-3-oxospiro[isoindoline-l ,4'-piperidine]-l '- carboxylate (50 mg, 0.12 mmol, 1.0 equiv) and TFA (7 mL) were heated to 75°C for 19 h. After this time LC-MS showed removal of the Boc- and p-methoxybenzyl groups. The mixture was concentrated to leave crude spiro[isoindoline-l,4'-piperidin]-3-one which was used directly. Step 2
  • Step 1 2.5 M n-BuLi in hexanes (9.2 mL, 23 mmol) was added To a stirred solution of
  • CDI A stirred solution of 2-adamantanamine hydrochloride (81.1 mg, 0.432 mmol) and DIEA (557 mg, 4.32 mmol) in anhydrous CH 2 CI 2 (5 mL) was cooled to 0 0 C and CDI (84 mg, 0.52 mmol) was added. The mixture was stirred for Ih at 0 0 C and tert- butyl spiro[indoline-3,4'-piperidine]-l-carboxylate (140 mg, 0.43 mmol) in anhydrous CH 2 Cl 2 (5 mL) was added. The reaction mixture was allowed to warm to it and stirred- overnight.
  • 1 H NMR (CDCl 3 ) ⁇ 2.05 (m, IH) 5 2.43 (m, IH) 5 2.60 (m, IH), 2.92 (m 5 IH), 3.05 (m, 2H) 5 3.65 (m, IH), 3.74 (s, 3H), 3.90 (d, IH) 5 4.00 (m, IH) 5 4.82 (d, IH).
  • Step 3 To a solution of N-(2-adamantyl)-l -hydroxy- 1 ,3-dihydros ⁇ iro[indene-2,3'- piperidine]-l'-carboxamide (20 mg, 0.052 mmol) in ethanol (3 mL) was added Pd(OH) 2 (10 mg), then the reaction mixture was stirred for 4 h at rt under a hydrogen atmosphere.
  • Step 3 A 25-mL of flask was charged with (2-adamantyl) 7-bromo-3-(2-ethoxy-2- oxoethyl)-2 5 3-dihydrospiro[indene-l,4'-piperidine]-r-carboxylate isomer 1 (100 mg, 0.19 mmol) dissolved in MeOH (3 mL). LiOH (10 mg, 0.38 mmol) dissolved in H 2 O (3 mL) was added and the mixture was stirred for 2 h at rt. The mixture was concentrated to remove MeOH. The aqueous layer was acidified with 1 N aq HCl (5 mL) and extracted with EtOAc (3 x 5 mL).
  • N-(3 5 5-dimethoxyben2yl)-4-oxoadamantane-l-carboxamide 230 mg, 0.670 mol
  • NaBH 4 100 mg, 2.7 mmol
  • the reaction mixture was stirred for 1 h at rt.
  • the solvent was removed under reduced pressure, diluted with CH 2 Cl 2 and washed with water.
  • the organic layer was separated, dried, and concentrated to give N-(3,5-dimethoxybenzyl)-4-hydroxyadamantane-l- carboxamide (230 mg, 100%).
  • Step 2 A solution of 4-aminoadamantan-l-ol (628 mg, 3.76 mmol) in dry CH 2 Cl 2 (2 mL) was added CDI (736 mg, 4.52 mmol) and DIEA (3.24 g, 25.12 mmol) at 0 0 C under N 2 and the mixture was stirred for 1 h. Ethyl 2-(7-bromo-2.3-dihydrospuO[indene-l,4'- piperidine]-3-yl)acetate (1.10 g, 3.14 mmol) was added and the mixture was stirred overnight. The mixture was washed with 5% aq HCl, and the organic layer was concentrated to give the crude product.
  • a mixture of isomers 1 and 2 of the title compound was prepared from a mixture of isomers 1 and 2 of ethyl 2-(7-bromo-r-((l-hydroxy-4-adamantyl)carbamoyl)-2,3- dihydrospiro[indene-l 5 4'-piperidine]-3-yl)acetate following a procedure analogous to that described in Example 66 Step 2.
  • Isomer 3 and 4 of the title compound were prepared from a mixture of isomers 3 and 4 of ethyl 2-(7-bromo-r-((l-hydroxy-4-adamantyl)carbamoyl)-2,3- dihydrospiro[indene-l 5 4'-piperidine]-3-yl)acetate and separated by preparative HPLC.

Abstract

This invention relates to novel compounds of the Formula (I*), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof which are useful for the therapeutic treatment of diseases associated with the modulation or inhibition of 11β- HSDl in mammals. The invention further relates to pharmaceutical compositions of the novel compounds and methods for their use in the reduction or control of the production of Cortisol in a cell or the inhibition of the conversion of cortisone to Cortisol in a cell.

Description

INHIBITORS OF llβ-HYDROXYSTEROIP DEHYDROGENASE TYPE 1
RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Application No. 60/840,203, filed August 25, 2006, the entire teachings of which are incorporated herein by reference.
FIELD OF THE INVENTION
The present invention relates to inhibitors of 11 β-hydroxy steroid dehydrogenase type 1 (llβ-HSDl1),' pharmaceutical compositions thereof and methods of using the same.
BACKGROUND OF THE INVENTION
Glucocorticoids, such as Cortisol (hydrocortisone), axe steroid hormones that regulate fat metabolism, function and distribution, and play a role in carbohydrate, protein and fat metabolism. Glucocorticoids are also known to have physiological effects on development, neurobiology, inflammation, blood pressure, metabolism and programmed cell death. Cortisol and other corticosteroids bind both the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR), which are members of the nuclear hormone receptor superfamily and have been shown to mediate Cortisol function in vivo. These receptors directly modulate transcription via DNA-binding zinc finger domains and transcriptional activation domains.
Until recently, the major determinants of glucocorticoid action were attributed to three primary factors: (1) circulating levels of glucocorticoid (driven primarily by the hypothalamic-pituitary-adrenal (HPA) axis); (2) protein binding of glucocorticoids in circulation; and (3) intracellular receptor density inside target tissues. Recently, a fourth determinant of glucocorticoid function has been identified: tissue-specific pre-receptor metabolism by glucocorticoid-activating and -inactivating enzymes. These 11 β- hydroxysteroid dehydrogenase (1 lβ-HSD) pre-receptor control enzymes modulate activation of GR and MR by regulation of glucocorticoid hormones. To date, two distinct isozymes of 11-beta-HSD have been cloned and characterized: 1 lβ-HSD 1 (also known as 11 -beta-HSD type 1, l lbetaHSDl , HSDI lBl, and HSDI lL) and 11 β-HSD2. 1 lβ-HSDl is a bi-directional oxidoreductase that regenerates active Cortisol from inactive 11 -keto forms, whereas 11 β-HSD2 is a unidirectional dehydrogenase that inactivates biologically active Cortisol by converting it into cortisone.
The two isoforms are expressed in a distinct tissue-specific fashion, consistent with the differences in their physiological roles. 1 lβ-HSDl is widely distributed in rat and human tissues; expression of the enzyme and corresponding rnRNA have been detected in human liver, adipose tissue, lung, testis, bone and ciliary epithelium. In adipose tissue, increased Cortisol concentrations stimulate adipocyte differentiation and may play a role in promoting visceral obesity. In the eye, 1 Iβ-HSDI may regulate intraocular pressure and may contribute to glaucoma; some data suggests that inhibition of 1 1 β-HSDl may cause a drop in intraocular pressure in patients with intraocular hypertension (Kotelevtsev, et al., (1997), Proc. Nat'l Acad. Sci. USA 94(26): 14924-9). Although 1 lβ-HSDl catalyzes both 1 1-beta-dehydrogenation and the reverse 1 1- oxoreduction reaction, 1 lβ-HSDl acts predominantly as a N ADPH-dependent oxoreductase in intact cells and tissues, catalyzing the formation of active Cortisol from inert cortisone (Low, et al., (1994) J. MoI. Endocrin. 13: 167-174). In contrast, 11 β- HSD2 expression is found mainly in mineralocorticoid target tissues such as kidney (cortex and medulla), placenta, sigmoid and rectal colon, salivary gland and colonic epithelial cell lines. 11 β-HSD2 acts as an N AD-dependent dehydrogenase catalyzing the inactivation of Cortisol to cortisone (Albiston, et al., (1994) MoI. Cell. Endocrin. 105:
Rl 1-Rl 7), and has been shown to protect the MR from glucocorticoid excess (e.g., high levels of receptor-active Cortisol) (Blum, et al., (2003) Prog. Nucl. Acid Res. MoI. Biol. 75:173-216).
Mutations in either the 1 lβ-HSDl or the 11 β-HSD2 genes result in human pathology. For example, individuals with mutations in 1 1 β-HSD2 are deficient in this cortisol-inactivation activity and, as a result, present with a syndrome of apparent mineralocorticoid excess (also referred to as "SAME") characterized by hypertension, hypokalemia, and sodium retention (Edwards, et al., (1988) Lancet 2: 986-989; Wilson, et al., (1998) Proc. Nat'l Acad. Sci. 95: 10200-10205). Similarly, mutations in 1 1 β- HSDl and in the gene encoding a co-localized NADPH -generating enzyme, hexose 6- phosphate dehydrogenase (H6PD), can result in cortisone reductase deficiency (CRD); these individuals present with ACTH-mediated androgen excess (hirsutism, menstrual irregularity, hyperandrogenism), a phenotype resembling polycystic ovary syndrome (PCOS) (Draper, et al., (2003) Nat. Genet. 34: 434-439).
Notably, disruption of homeostasis in the HPA axis by either deficient or excess secretion or action results in Cushing's syndrome or Addison's disease, respectively (Miller & Chrousos, Endocrinology and Metabolism (Felig & Frohman eds., McGraw- Hill: New York, 4th Ed. (2001)) 387-524). Patients with Cushing's syndrome or receiving glucocorticoid therapy develop reversible visceral fat obesity. The phenotype of Cushing's syndrome patients closely resembles that of Reaven's metabolic syndrome (also known as Syndrome X or insulin resistance syndrome), the symptoms of which include visceral obesity, glucose intolerance, insulin resistance, hypertension, type 2 diabetes and hyperlipidemia (Reaven, (1993) Ann. Rev. Med. 44, 121-131). Although the role of glucocorticoids in human obesity is not fully characterized, there is mounting evidence that 1 lβ-HSDl activity plays an important role in obesity and metabolic syndrome (Bujalska, et al., (1997) Lancet 349: 1210-1213); (Livingstone, et al., (2000) Endocrinology 131, 560-563 ; Rask, et al., (2001 ) J. Clin. Endocrinol. Metab. 86, 1418- 1421; Lindsay, et al., (2003) J. Clin. Endocrinol. Metab. 88: 2738-2744; Wake, et al., (2003) J. Clin. Endocrinol. Metab. 88, 3983-3988).
Data from studies in mouse transgenic models supports the hypothesis that adipocyte 1 lβ-HSDl activity plays a central role in visceral obesity and metabolic syndrome (Alberts, et al., (2002) Diabetologia. 45(11), 1526-32). Over-expression in adipose tissue of 1 lβ-HSDl under the control of the aP2 promoter in transgenic mice produced a phenotype remarkably similar to human metabolic syndrome (Masuzaki, et al., (2001) Science 294, 2166-2170; Masuzaki, et al., (2003) J. Clinical Invest. 112, 83- 90). Moreover, the increased activity of 1 lβ-HSDl in these mice is very similar to that observed in human obesity (Rask, et al., (2001) J. Clin. Endocrinol. Metab. 86, 1418- 1421). In addition, data from studies with 1 lβHSDl -deficient mice produced by homologous recombination demonstrate that the loss of 1 lβ-HSDl leads to an increase in insulin sensitivity and glucose tolerance due to a tissue-specific deficiency in active glucocorticoid levels (Kotelevstev, et al., (1997) Proc. Nat'l Acad. Sci. 94: 14924-14929; Morton, et al., (2001) J. Biol. Chem. 276, 41293-41300; Morton, et al., (2004) Diabetes 53, 931-938).
The published data supports the hypothesis that increased expression of 1 lβ- HSDl contributes to increased local conversion of cortisone to Cortisol in adipose tissue and hence that 1 lβ-HSDl plays a role in the pathogenesis of central obesity and the appearance of the metabolic syndrome in humans (Engeli, et al., (2004) Obes. Res. 12: 9- 17). Therefore, 1 lβ-HSDl is a promising pharmaceutical target for the treatment of the metabolic syndrome (Masuzaki, et al., (2003) Curr. Drug Targets Immune Endocr. Metabδl. Disord. 3: 255-62). Furthermore, inhibition of 1 lβ-HSDl activity may prove beneficial in treating numerous glucocorticoid-related disorders. For example, 11 β- HSDl inhibitors could be effective in combating obesity and/or other aspects of the metabolic syndrome cluster, including glucose intolerance, insulin resistance, hyperglycemia, hypertension, and/or hyperlipidemia (Kotelevstev, et al., (1997) Proc. Nat'I Acad. Sci. 94, 14924-14929; Morton et al., (2001) J. Biol. Chem. 276, 41293- 41300; Morton, et al., (2004) Diabetes 53, 931-938). In addition, inhibition of 1 lβ- HSDl activity may have beneficial effects on the pancreas, including the enhancement of glucose-stimulated insulin release (Billaudel & Sutter, (1979) Horm. Metab. Res. 1 1, 555-560; Ogawa, et al., (1992) J. Clin. Invest. 90, 497-504; Davani, et al., (2000) J. Biol. Chem. 275, 34841-34844). Inter-individual differences in general cognitive function has been linked to variability in the long-term exposure to glucocorticoids (Lupien, et al., (1998) Nat. Neurosci. 1: 69-73) and dysregulation of the HPA axis. Such chronic exposure to glucocorticoid excess in certain brain subregions has been theorized to contribute to the decline of cognitive function (McEwen & Sapolsky (1995) Curr. Opin. Neurobiol. 5, 205-216). Therefore, inhibition of 1 lβ-HSDl may reduce exposure to glucocorticoids in the brain and thereby protect against deleterious glucocorticoid effects on neuronal function, including cognitive impairment, dementia, and/or depression.
There is also evidence that glucocorticoids and 1 lβ-HSDl play a role in regulation of in intra-ocular pressure (IOP) (Stokes et al., (2000) Invest. Ophthalmol. Vis. Sci. 41: 1629-1683; Rauz, et al., (2001) Invest. Ophthalmol. Vis. Sci. 42: 2037-
2042). If left untreated, elevated IOP can lead to partial visual field loss and eventually blindness. Thus, inhibition of 1 lβ-HSDl in the eye could reduce local glucocorticoid concentrations and IOP, and hence could be used to treat or prevent glaucoma and other visual disorders. Transgenic aP2-l 1 β-HSDl mice exhibit high arterial blood pressure and have increased sensitivity to dietary salt. Additionally, plasma angiotensinogen levels are elevated in the transgenic mice, as are angiotensin II and aldosterone. Treatment of the mice with an angiotensin II antagonist alleviates the hypertension (Masuzaki, et al., (2003) J. Clinical Invest. 112, 83-90). This suggests that hypertension may be caused or exacerbated by 1 Iβ-HSDI activity. Thus, llβ-HSDl inhibitors may be useful for treatment of hypertension and hypertension-related cardiovascular disorders.
Glucocorticoids can have adverse effects on skeletal tissues, and prolonged exposure to even moderate glucocorticoid "doses can result in osteoporosis (Cannalis, (1996) J. Clin. Endocrinol. Metab. 81, 3441-3447). In addition, 1 l β-HSDl has been shown to be present in cultures of human primary osteoblasts as well as cells from adult bone (Cooper, et al., (2000) Bone 27: 375-381), and the 1 lβ-HSDl inhibitor carbenoxolone has been shown to attenuate the negative effects of glucocorticoids on bone nodule formation (Bellows, et al., (1998) Bone 23 : 119-125). Thus, inhibition of 1 Iβ-HSDI is predicted to decrease the local glucocorticoid concentration within osteoblasts and osteoclasts, thereby producing beneficial effects in various forms of bone disease, including osteoporosis.
As evidenced herein, there is a continuing need for new and improved drugs that inhibit 1 lβ-HSDl . The novel compounds of the present invention are effective inhibitors of l lβ-HSDl .
SUMMARY QF THE INVENTION
The present invention provides compounds of Formula I*:
Figure imgf000006_0001
wherein: K, L, M, X and Y are independently C, N or O5 provided that the total number of nitrogen and oxygen atoms in the ring is 3 or less and when K3 L, M5 X or Y is O, any adjacent member atom in the ring cannot be O; the bonds between K, L5 M, X and Y are single or double bonds provided that no consecutive double bonds occur between member atoms of the ring; n= 0, I5 or 2; s = 1 or 2; t = 1 or 2;
R1 - R^ are independently hydrogen, A-(5-tetrazolyl), A-(cycloalkyl), A-(heteroaryl)5 A-(heterocyclyl), A-(aryl), A-COOR6, A-CON(R6)2, A-COR6, A-SO2R6, A-CONHSO2R6, A-CONHSO2OR6, A-CONHS O2N(R6)2, A-C=N, alkyl, alkenyl, cycloalkyl, heteroaryl, heterocyclyl, aryl or arylalkyl, wherein the alkyl, alkenyl, cycloalkyl, heteroaryl, heterocyclyl, aryl, A-(cycloalkyl), A-(heteroaryl), A-(heterocyclyl), A-(aryl) or arylalkyl groups represented by R1 - R5 are optionally and independently substituted with 1-3 groups independently selected from the group consisting of halogen, hydroxy, cyano, -N(R6)2, -NR6C(O)N(R6)2, -NR6C(O)R6, (C1- QOalkyl, halo(C1-C6)alkyl, (Ci-C6)alkoxy, halo (C,-C6)alkoxy, CONH2, -SO2R6, -NR6SO2R6, -NR6SO2N(R6)2 and -NR6SO2OR6; when K, L, M, X, or Y is (-O-) or (-N=), then pi, p2, p3, p4 or p5, respectively, is O; when K, L, M, X, or Y is (-N-), (-C=), or (-CH-), then pi, p2, ρ3, p4 or p5, respectively, is 1 ; when K5 L, M, X or Y is (-C-), then pi, p2, p3, p4 or p5, respectively, is 2; and when K, L, M, X, or Y is (-C-), and R1, R2, R3, R4 or R5 is connected through a double bond to K, L, M, X or Y, respectively, then pi, p2, p3, p4 or p5, respectively, is i; A is a single bond, (Ci-C6)alkylene, (Ci-C6)alkenylene, (Ci-
C5)alkylCH=,C(0)(Co-C3)alkyl(C3-C6)cycloalkyl(Co-C3)alkylene, C(O)(C 1-C6)alkylene, C(O)(C2-C6)alkenylene, S(O)2(Cj -C6)alkylene, S(O)2(C2-C6)alkenylene, or S(O)2(C0- C3)alkyl(C3-C6)cycloalkyl(Co-C3)alkylene, each optionally substituted with up to 4 groups, R6; R1, K, L and R2 are taken together to form a fused benzene or pyridine ring, which is optionally substituted with 1-3 groups independently selected from the group consisting of halogen, hydroxy, cyano, -N(R6)2, -NR6C(O)N(R6)2, -NR6C(O)R6, (Ci- C6)alkyl, halo(C,-C6)alkyl, (C,-C6)alkoxy, halo(C]-C6)alkoxy, CON(R6)2, SO2N(R6)2, -SO2R6, -NR6SO2R6, -NR6SO2N(R6);. and -NR6SO2OR6; or
R2, L, M and R3 are taken together to form a fused benzene or pyridine ring, which is optionally substituted with 1-3 groups independently selected from the group consisting of halogen, hydroxy, cyano, -N(R6)2, -NR6C(O)N(R6)2, -NR6C(O)R6, (C1- C6)alkyl, halo(Cj-C6)alkyl, (Cj-C6)alkoxy5 halo(C,-C6)alkoxy, CON(R6)2, SO2N(R6)2, -SO2R6, -NR6SO2R6, -NR6SO2N(R6)2 and -NR6SO2OR6; or
R2, L5 X and R4 are taken together, when n = O, to form a fused benzene or pyridine ring, which is optionally substituted with 1-3 groups independently selected from the group consisting of halogen, hydroxy, cyano, -N(R6)2, -NR6C(O)N(R6)2, -NR6C(O)R6, (CrC6)alkyl, halo(CrC6)alkyl, (CrC6)alkoxy, halo(CrC6)alkoxys CON(R6)2, SO2N(R6)2, -SO2R6, -NR6SO2R6, -NR6SO2N(R6), and -NR6SO2OR6, provided that n = O and M and R3 are absent; or
R4, X, Y and R5 are taken together to form a fused benzene or pyridine ring, which is optionally substituted with 1-3 groups independently selected from the group consisting of halogen, hydroxy, cyano, -N(R6)2, -NR6C(O)N(R6)2, -NR6C(O)R6, (C,- C6)alkyl5 halo(C,-C6)alkyl, (C,-C6)alkoxy, halo(CrC6)alkoxy, CON(R6)2, SO2N(R6)2, -SO2R6, -NR6SO2R6, -NR6SO2N(R6)2 and -NR6SO2OR6; or the group consisting of R1, K, L and R2 and the group consisting of R4, X, Y and R5 are each taken together to form a fused benzene or pyridine ring, each of which is optionally substituted with 1 -3 groups independently selected from the group consisting of halogen, hydroxy, cyano, -N(R6)2, -NR6C(O)N(R6)2, -NR6C(O)R6, (Ci-C6)alkyl3 halo(Ci-C6)alkyl, (Ci-C6)alkoxy, halo(Ci-C6)alkoxy, CON(R6)2s SO2N(R6)2, -SO2R6, -NR6SO2R6, -NR6SO2N(R6)2 and -NR6SO2OR6; R6 is hydrogen, (C)-C10)alkyl, halo(C]-Ci0)alkyl, hydroxy(CrCi0)alkyl,
(R6)2N(Ci-Cio)alkyl, aryl or arylalkyl, wherein the aryl and arylalkyl groups are optionally substituted with up to three groups independently selected from halogen, hydroxy, cyano, -N(R6)2, -NR6C(O)N(R6)2, -NR6C(O)R6, (CrC6)alkyl, halo(CrC6)alkyl, (Ci-C6)alkoxy, halo(CrC6)alkoxy, CON(R6)2, SO2N(R6)2, -SO2R6, -NR6SO2R6, -NR6SO2N(R6)2 and -NR6SO2OR6; or
N(R6)2 is a heterocyclyl group containing at least one nitrogen atom, preferably selected from W1 - W7:
Figure imgf000009_0001
W1 W2 W3 W4
Figure imgf000009_0002
W5 W6 W7
Q is O or NR6; and
R7 is a saturated C7-C12 bicycloalkyl or saturated C9-C12 tricycloalkyl in which 1- 2 carbon atoms are optionally replaced with heteroatoms independently selected from N and O5 and which is optionally substituted with 1-3 substituents independently selected from the group consisting of R6, heteroaryl, oxo-substituted heteroaryl, amino- substituted heteroaryl, heterocyclyl, oxo-substituted heterocyclyl, halogen, hydroxy, hydroxy(C,-C6)alkyl5 C(NOH)NH2, CONHR6, CH2CONHR6, CON(R6)2, CH2CON(R6)2, SO2NHR6, SO2N(R6)2, CO2R6, CH2CO2R6, SO2R6, NHCOR6, NR6COR6, NHCO2R6, NR6CO2R6, NHSO2R6, and NR6SO2R6; or an enantiomer, diastereomer, geometrical isomer or pharmaceutically acceptable salt thereof; optionally, with the general provisos that:
(1) if R1, K5 L and R2 form a fused benzene or pyridine ring. Q is NR6, R6 is H, Y is O, s = I51 = 2, n = O, X is C, R4 is H and R5 is absent, then R7 is not a 7- to 10- membered carbocyclic group or heterocyclic group;
(2) if R1, K, L and R2 form a fused benzene ring, Q is NR6. R6 is H, n = 1, s = I5 t = 1 or 2, and M, X and Y are all carbon, then at least one of R3, R4 or R5 must not be -(CH2)n-Z, wherein n=0 to 2, and Z is hydrogen, (Ci-C6)alkyl, 2-pyridyl, 3-pyridyl, A- pyridyl or substituted or unsubstituted phenyl wherein if the phenyl is substituted, there are 1 or 2 substituents independently selected from the group consisting of halogen, (Cr C6)alkyl, (Ci-C6)alkoxy, carboxyl, cyano, loweralkylthio, carboxy-loweralkyl, nitro, - CF3 or hydroxy. Preferably, if R1, K, L and R2 form a fused benzene ring, Q is NR6, R6 is H, n = 1, s = 1, t = 1 or 2, and M, X and Y are all carbon, then at least one of R3, R4 or R5 must not be -(CHa)n-Z, wherein n=0 to 2, and Z is hydrogen, Ci -Cβ alkyl, 2-pyridyl, 3- pyridyl, 4-pyridyl or substituted or unsubstituted phenyl; and (3) if R1 , K, L and R2 form a fused benzene ring, Q is NR6, R6 is H, n = 0, s = 1 , t = 1 or 2, X is C or O and Y is C or O5 then at least one of R4 or R5 must not be -CH2)O-Z, wherein n=0 to 2, and Z is hydrogen, (Ci-C6)alkyl, 2-pyridyl. 3-pyridyls 4-pyridyl or substituted or unsubstituted phenyl wherein if the phenyl is substituted, there are 1 or 2 substituents independently selected from the group consisting of halogen, (C]-C6)alkyl, (d-C6)alkoxy, carboxyl, cyano, loweralkylthio, carboxy-loweralkyl, nitro, -CF3 or hydroxy. Preferably, if R1, K5 L and R2 form a fused benzene ring, Q is NR6, R6 is H, n = O5 s = 1, t = 1 or 2, X is C or O and Y is C or O, then at least one of R4 or R5 must not be -CEb)n-Z wherein n=0 to 2, and Z is hydrogen, (Ci-Cό)alkyl5 2-pyridyl, 3-pyridyl, 4- pyridyl or substituted or unsubstituted phenyl.
Additionally, embodiments of Formula I* can optionally have the following provisos:
4) if R1, K, L and R2 form a fused benzene ring: Q is O or NR6; R6 is H, phenyl, (Ci-Cg)alkyl, halo(C1-C8)alkyl5 or hydroxy(CrCs)alkyl; s = 1 or 2; t = 1 or 2; and 1) n is 0, X is C, and Y is N or O, 2) n is 1, X is N or O, Y is C, and M is C, or 3) n is 2, X is C, Y is C, and the M α to the fused benzene is C and the M β to the fused benzene is N or O; then R7 must not be C7-C12 bicycloalkyl or Cp-Ci2 tricycloalkyl;
5) if R1, K, L and R2 form a fused benzene ring; R4 is H; R5 is H; Q is NH; s = 1, t = 2; n = 0; X is C; Y is C; there is an optional double bond between X and Y; then R7 must not be substituted bicyclo[2.2.2]octane or substituted bicyclo[2.2.1 jheptane;
6) if R1, K5 L and R2 form a fused benzene or pyridine ring; X is N; Y is C; n — 0, 1; M, when present, is C; s = 1 or 2; t = 1 or 2; Q is O or NR6; R6 is (Ci-C6)alkyl; then R7 must not be (^-C^bicylcoalkyl or (C9-Ci2)tricycloalkyl, wherein the bicycloalkyl and tricycloalkyl are carbocycles; and
7) if R1, K, L and R2 form a fused benzene ring; t = 1 , 2; s = 1 , 2; Q = NR6; R6 =
H5 (Ci-Cjo)alkyl, halo(Ci-Cio)alkyl, hydroxy(CrCi0)alkyl, phenyl or arylalkyl; and 1) n = O5 X is C5 N5 or O5 and Y is C; or 2) n = 1 ; M is C3 N5 or O; X = C5 and Y = C; then R7 must not be adamantyl, a bridged (C6-Cs)bicycloalkyl or a (C9-Cj2)tricycloalkyl wherein one cycloalkyl of the tricycloalkyl moiety is fused to a bridged bicycloalkyl moiety. It is understood that provisos 1-7 can be suitably applied to all embodiments of the invention described herein. It is further understood that, depending on the embodiment of the invention, one or more of provisos 1-7 (i.e., any combination of provisos) can optionally be included in the description of any embodiment. For example, provisos 4. 5, 6, or 7 can be individually applied to any embodiment; provisos 4 and 5, 4 and 6, or 4 and 7 can be applied in combination to any embodiment; provisos 5 and 6 or 5 and 7 can be applied in combination to any embodiment; provisos 6 and 7 can be applied in combination to any embodiment; provisos 4, 5 and 6 can be applied in combination to any embodiment; provisos 4, 5 and 7 can be applied in combination to any embodiment; provisos 4, 6 and 7 can be applied in combination to any embodiment; provisos 5, 6 and 7 can be applied in combination to any embodiment; or provisos 4, 5, 6 and 7 can be applied in combination to any embodiment.
Another embodiment of the invention is a compound of Formula I:
Figure imgf000011_0001
wherein:
K5 L, M, X and Y are independently C, N or O, provided that the total number of nitrogen and oxygen atoms in the ring is 3 or less and when K, L5 M, X or Y is O5 any adjacent member atom in the ring cannot be O; the bonds between K5 L, M5 X and Y are single or double bonds provided that no consecutive double bonds occur between member atoms of the ring; n= 0, I5 or 2; s = 1 or 2; t = 1 or 2; R1 - R5 are independently hydrogen, A-(5-tetrazolyl), A-COOR6, A-CON(R6)2. A-COR6, A-SO2R6, A-CONHSO2R6, A-CONHSO2N(R6)2, A-Cs(N, alkyl, cycloalkyl, heteroaryl, aryl or arylalkyl, wherein the cycloalkyl, heteroaryl, aryl or arylalkyl groups represented by R'-Rs are optionally and independently substituted with 1-3 groups independently selected from the group consisting of halogen, cyano, (Ci-C6)alkyl, halo(Ci-C6)alkyl, CONH2 and NR6SO2R6, except that any one or more of R1 - R5 is absent where the atom to which such R1 - R5 group would otherwise be connected is (i) O, or (ii) an N that is connected by a double bond to an adjacent atom;
A is a single bond, C(R6)2 or C(R6)2C(R6)2; R1 , K, L and R2 are taken together to form a fused benzene or pyridine ring, each of which is optionally substituted with 1-3 groups independently selected from the group consisting of halogen, cyano, (Ci-C6)alkyl, halo(Ci-C6)atkyl, (Cj-C6)alkoxy, halo(Ci- C6)alkoxy, CONH2 and NR6SO2R6; or
R2, L3 M and R3 are taken together to form a fused benzene or pyridine ring, each of which is optionally substituted with 1 -3 groups independently selected from the group consisting of halogen, cyano, (d-C^alkyl, halo(Ci-C6)alkyl, (Ci-C6>alkoxy, halo(Ci- C6)alkoxy, CONH2 and NR6SO2R6; or
R2, L, X and R4 are taken together, when n = O5 to form a fused benzene or pyridine ring, each of which is optionally substituted with 1-3 groups independently selected from the group consisting of halogen, cyano, (Cj-C6)alkyl. halo(C]-C6)alkyl3 (Ci-C6)alkoxy, halo(Ci-C6)alkoxy, CONH2 and NR6SO2R6 provided that n = O and M and R3 are absent; or
R4, X, Y and R5 are taken together to form a fused benzene or pyridine ring, each of which is optionally substituted with 1-3 groups independently selected from the group consisting of halogen, cyano, (CVC^alkyl, halo(C]-C6)alkyl, (Ci-C^alkoxy, halo(Ci- C6)alkoxy, CONH2 and NR6SO2R6; or the group consisting of R1, K3 L and R2 and the group consisting of R4. X, Y and R5 are each taken together to form a fused benzene or pyridine ring, each of which is optionally substituted with 1-3 groups independently selected from the group consisting of halogen, cyano, (d-C6)alkyl3 halo(CrC6)alkyl, (Ci-C6)alkoxy, halo(Ci-C6)alkoxy, CONH2 and NR6SO2R6;
R6is hydrogen, (Ci-Cio) alkyl, aryl or arylalkyl; Q is O or NR6; R7 is a saturated C7-Ci2 bicycloalkyl or saturated Cg-Ci2 tricycloalkyl in which 1- 2 carbon atoms are optionally replaced with heteroatoms independently selected from N and O, and which is optionally substituted with 1-3 substituents independently selected from the group consisting of R6, heteroaryl, oxo-substituted heteroaryl, amino- substituted heteroaryl, heterocyclyl, oxo-substituted heterocyclyl, halogen, hydroxy, hydroxymethyl, C(NOH)NH2, CONHR6, CH2CONHR6, CON(R6)2, CH2CON(R6)2, SO2NHR6, SO2N(R6)2, CO2R6, CH2CO2R6, SO2R6, NHCOR6, NR6COR6, NHCO2R6, NR6CO2R6, NHSO2R6, and NR6SO2R6; or an enantiomer, diastereomer, geometrical isomer or pharmaceutically acceptable salt thereof; with the general provisos that:
(1) if R1, K, L and R2 form a fused benzene or pyridine ring, Q is NR6, R6 is H5 Y is O, s = 1, t = 2, n = O5 X is C, R4 is H and R5 is absent, then R7 is not a 7- to 10- membered carbocyclic group or heterocyclic group;
(2) if R1, K, L and R2 form a fused benzene ring, Q is NR6, R6 is H, n = 1, s = 1, t = 1 or 2. and M, X and Y are all carbon, then at least one of R3, R4 or R5 must not be
-(CH2)H-Z, wherein n=0 to 2, and Z is hydrogen, (Cj-C6)alkyl, 2-pyridyl, 3-pyridyl, A- pyridyl or substituted or unsubstituted phenyl wherein if the phenyl is substituted, there are 1 or 2 substituents independently selected from the group consisting of halogen, (Ci- C6)alkyl, (Ci-C6)alkoxy, carboxyl, cyano, loweralkylthio, carboxyloweralkyl, nitro, -CF3 or hydroxy. Preferably, if R1. K, L and R2 form a fused benzene ring, Q is NR6, R6 is H, n = 1, s = 1, t = 1 or 2, and M, X and Y are all carbon, then at least one of R3, R4 or R5 must not be -(CH2)D-Z, wherein n=0 to 2, and Z is hydrogen, Ci-C6 alkyl, 2-pyridyl, 3- pyridyl, 4-pyridyl or substituted or unsubstituted phenyl; and
(3) if R1 , K, L and R2 form a fused benzene ring, Q is NR6, R6 is H, n = O, s = 1 , t = 1 or 2, X is C or O and Y is C or O, then at least one of R4 or R5 must not be be
-(CH2)n-Z, wherein n=0 to 2. and Z is hydrogen, (Ci-C6)alkyl, 2-pyridyl, 3-pyridyl, A- pyridyl or substituted or unsubstituted phenyl wherein if the phenyl is substituted, there are 1 or 2 substituents independently selected from the group consisting of halogen, (C1- Cβ)alkyl, (Ci-C6)alkoxy, carboxyl, cyano, loweralkylthio, carboxyloweralkyl, nitro, -CF3 or hydroxy. Preferably, if R1, K, L and R2 form a fused benzene ring, Q is NR6, R6 is H, n = O, s = 1 , t = 1 or 2, X is C or O and Y is C or O, then at least one of R4 or R3 must not be be -CBb)n-Z wherein n=0 to 2, and Z is hydrogen, (CrC6)alkyl, 2-pyridyl, 3-pyridyl, 4-pyridyl or substituted or unsubstituted phenyl.
Additionally, embodiments of Formula I can optionally have the following provisos:
'5 4) if R1, K, L and R2 form a fused benzene ring; Q is O or NR6; R6 is H. phenyl,
(CrC8)alkyl, halo(Ci-C8)alkyl, or hydroxy(Ci-C8)alkyl; s = 1 or 2; t = 1 or 2; and 1) n is O3 X is C, and Y is N or O, 2) n is 1 , X is N or O, Y is C. and M is C, or 3) n is 2, X is C, Y is C, and the M α to the fused benzene is C and the M β to the fused benzenαis N or O; then R7' must not be C7-Cj2 bieycloalkyl or C9-Ci2 tricycloalkyl; 0 5) if R1, K, L and R2 form a fused benzene ring; R4 is H; R5 is H; Q is NH: s = 1, t = 2; n = 0; X is C; Y is G; there is an optional double bond between X and Y; then R7 must not be substituted bicyclo[2.2.2]octane or substituted bicyclo[2.2.1]heptane;
6) if R1, K, L and R2 form a fused benzene or pyridine ring; X is N; Y is C; n = 0, 1; M, when present, is C; s = 1 or 2; t = 1 or 2; Q is O or NR6; R6 is (Ci-C6)alkyl; then R75 must not be (C7-Ci2)bicylcoalkyl or (C9-Ci2)tricycloalkyl, wherein the bieycloalkyl and tricycloalkyl are carbocycles; and
7) if R1, K5 L and R2 form a fused benzene ring; t = I5 2; s = I5 2; Q = NR6; R-6 = H, (Ci-Cjo)alkyl, halo(Ci-Cio)alkyl. hydroxy(C]-Cio)alkyl, phenyl or arylalkyl; and 1) n = 0, X is C5 N, or O, and Y is C; or 2) n = 1; M is C5 N5 or O; X = C5 and Y = C; then R70 must not be adamantyl, a bridged (C6-Cs)bicycloalkyl or a
Figure imgf000014_0001
wherein one cycloalkyl of the tricycloalkyl moiety is fused to a bridged bieycloalkyl moiety.
Preferred compounds of the invention are those of any embodiment of Formulae I* or ϊ where none of K, L, M5 X, and Y is a basic N, and the remainder of the variables are defined above. 5 Also preferred are compounds of any embodiment of Formulae I* or I where R1,
K, L and R2 form a fused benzene ring, and the remainder of the variables are defined above.
Additionaly compounds of the invention are those of any embodiment of Formulae I* or I wherein K, L5 M5 X5 and Y are individually C or O; R! — R5 are independently H or alkyl; and/or the bonds between K, L5 M5 X, and Y are all single bonds, and the remainder of the variables are defined above.
Other compounds of the invention are those of any embodiment of Formula I* or I, wherein Q is O or NH, and the remainder of the variables are defined above. Other preferred compounds of the invention are those of Formula I* or I wherein
Q is NR6 or O, R6 is H and/or R7 is 2-adamantyl, l-hydroxy-4-adamantyl, 1- hydroxymethyl-4-adamantyl, 1 -carbamoyl-4-adamantyl, 1 -(methylsulfonyl)-4- adamantyl, l-(aminosulfonyl)-4-adamantyl. 1 -bicyclo[2.2.2]octyl, l-carbamoyl-4- bicyclo[2.2.2]octyl, 9-bicyclo[3.3.1]nonyl or 3-carbamoyl-9-bicyclo[3.3J ]nonyL and the remainder of the variables are defined above.
Other preferred compounds are those of Formual I* or I, wherein Q is O and/or R7 is selected from the group consisting of 2-adamantyl, l-hydroxy-4-adamantyl, 1- hydroxymethyl-4-adamantyl, and 1 -carbamoyl-4-adamantyl, and the remainder of the variables are defined above. Also preferred compounds are those of Formula I* or I, wherein n is O5 s is 1 , and/or t is 2, and the remainder of the variables are defined above.
Specific examples of compounds of the invention are: tert-Butyl 1 l-((2-adamantyl)carbamoyl)spiro[indoline-3,4'-piperidine]-] - carboxylate;
N-(2-Adamantyl)spiro[indoline-3,4'-piperidine]-r-carboxamide;
(+)-2-(r-((2-Adamantyl)carbamoyl)-2,3-dihydrospiro[indene-l,4'-piperidine]-3- yl)acetic acid;
(±)-Methyl 2-(l '-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-l .4'- piperidine]-3-yl)acetate;
(R)-Methyl 2 -(I '-((2-adamantyl)carbamoyl)-2,3-dihydrosρiro[indene-l ,4'- piperidine] -3 -yl)acetate;
(S)-Methyl 2-(r-((2-adamantyl)carbamoyl)-2.3-dihydrospiro[mdene-l,4'- piperidine]-3-yl)acetate; 2-(r-((2-Adamantyl)carbamoyl)-2,3-dihydrospiro[indene-l,4'-piperidine]-3- yl)acetic acid, isomer B; l-Acetyl-N-(2-adamantyl)spiro[indoline-3,4'-piperidine]-r-carboxamide;
1 '-((2-Adamantyl)carbamoyl)spiro [indene- 1 ,4'-piperidine]-3-carboxylic acid; (±)-r-((2-Adamantyl)carbajnoyl)-2,3-dihydrospiro[indeπe-l,4'-piperidine]-3- carboxylic acid;
(±)- 1 '-((2-Adamantyl)carbamoyl)-2,3 -dihycfrospirofindene- 1 ,4'-piperidine]-3 - carboxylic acid; Ethyl 1 '-((2-adamantyl)carbamoyl)spiro[indene-l ,4'-piperidine]-3-carboxylate;
(±)-Ethyl 1 '-(cyclohexylcarbamoyl)-2,3-dihydrospiro[indene-l ,4'-piperidine]-3- carboxylate;
N-(2-Adamantyl)-l -(methylsulfonyl)spiro[indoline-3,4'-piperidine]- 1 '- carboxamide; 2-adamantyl spiro[indoline-3,4'-piperidine]-l '-carboxylate;
2-adamantyl 5-fluorospiro[indoline-354'-piperidme]-r-carboxylate: 2-adamantyl 5-methylspiro[indoline-3,4'-piperidine]-l '-carboxylate; 2-adamantyl 1 -acetylspiro[indolme-3,4'-piperidine]-r-carboxylate; ■ (±)-2-adamantyl 3-(2-methoxy-2-oxoethyl)-2,3-dibydrospiro[indene- 1 ,4'- piperidine]-r-carboxylate;
(±)-2-(r-((2-adamantyloxy)carbonyl)-2,3-dihydrospϊro[indene-l:,4'-piperidine]-3- yl)acetic acid; and
(±)-2-adamantyl 3-(2-(methylamino)-2-oxoethyl)-2,3-dihydrospiro[indene-l54.'- piperidine]-l '-carboxylate; or an enantiomer, diastereomer, geometrical isomer or pharmaceutically acceptable salt thereof reof.
Additional examples of compounds of the invention are:
2-(l '-((2-Adamantyl)carbamoyl)-253-dihydrospiro[indene- 1.4'-piperidine]-3- yl)acetic acid; N-(2-adamantyl)-l,3-dihydrospiro[indene-2,3'-piperidine]-r-carboxam.ide;
N-(2-adamantyl)-2,3-dihydrospiro[indene-l,4'-piperidine]-l '-carboxamide; tert-butyl 1 '-((2-adamantyl)carbamoyl)-lH-spiro[isoquinoline-4,4'-piperidine]- 2(3H)-carboxylate;
N-(2-adamantyl)-253 -dihydro- 1 H-spiro[isoquinoline-4,4'-piperidine] - 1 '- carboxamide;
2-acetyl-N-(2-adamantyl)-2,3-dihydro-l H-spiro[isoqumoline-454'-piperidine]- 1 '- carboxamide: ethyl 3-(r-((2-adamaπtyl)carbamoyl)-lH-spiro[isoquinoline-4,4l-piperidine]- 2(3H)-yl)propanoate;
3-(r-((2-adamantyl)carbamoyl)-lH-spiro[isoquinoline-4,4'-piperidine]-2(3H)- yl)propanoic acid; N-(2-adamantyl)-2-(methylsulfonyl)-2,3-dihydro- 1 H-spiro[isoquinoline-4J41- piperidine] - 1 '-carboxarnide ;
N 1 t-(2-adamantyl)-N2-methyl- lH-spiro[isoquinoline-4.4'-piperidine]-l ',2(3H)- dicarboxamide: ethyl r-((2-adamantyl)carbamoyl)-lH-spiro[isoquinoline-4,4'-piperidine]-2(3H)- carboxylate;
2-tert-butyl l'-(2-adamantyl) lH-spiro[isoqumoline-4,4'-piperidine]-r.2(3H)- di carboxylate;
2-adamantyl 2,3-dihydro-lH-spiro[isoquinoline-4.4'-piperidine]- 1 '-carboxylate;
2-adamantyl 2-(methylsulfonyI)-2,3-dihydro- 1 H-spiro[isoquinoline-4,4'- piperidine]- 1 '-carboxylate;
2-adamantyl 2-(isopropylsulfonyl)-253-dihydro-lH-spiro[isoquinoline-4,4'- piperidine] - 1 '-carboxylate;
2 -adamantyl 2 -(5 -cyanopyridin-2 -yl)-2, 3 -dihydro- 1 H-spiro [isoquinoline-4,41- piperidine]-l '-carboxylate; (±)-ethyl 2-(7-bromo-l '-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-l ,4'- piperidine] -3 -yl)acetate ;
(-t)-2-(7-bromo-r-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-'l,4'- piperidine]-3-yl)acetic acid;
2-(7-bromo-r-((2-adamantyl)carbamoyl)-2:,3-dihydrospirό[indene-l,4'- piperidine] -3 -yl) acetic acid, isomer 1;
2-(7-bromo- 1 '-((2-adamantyI)carbamoyl)-253-dihydrospiro [indene- 1 ,4'- piperidine]-3-yl)acetic acid, isomer 2;
(±)-N-(2-adamantyl)-3-(2-(methylsulfonamido)-2-oxoethyl)-2,3- dihydrospiro[indene-l,4'-piperidine]-r-carboxamide; (±)-3-(cyanomethyl)-N-cyclohexyl-2:,3-dihydrospiro[indene-l,4'-piperidine]-r- carboxamide;
(±)-3-((lH-tetrazol-5-yl)methyl)-N-(2-adaraantyl)-253-dihydrospiro[indene-l,4r- piperidinej-l '-carboxamide; (±)-ethyl 2-(l '-((2-adamantyl)carbamoyl)-7-methyl-2,3-dihydrospiro[indene-l ,4'- piperidine] -3 -y l)acetate;
(±)-2-( 1 '-((2-adamantyl)carbamoy l)-7-methyl-2,3 -dihydrospiro [indene- 1 ,4'- piperidine]-3-yl)acetic acid; (±)-ethyl 2-(l '-((2-adamantyl)carbamoyl)-4-methyl-2,3-dihydrospiro[indene-ls4'- piperidine] -3 -y l)acetate;
(±)-2-(r-((2-adamantyl)carbamoyl)-4-methyl-2,3-dihydrospiro[indene-l}4'- piperidine]-3-yl)acetic acid;
(±)-ethyl 2-(l '-((2-adamantyl)carbamoyl)-7-chloro-253-dihydrospiro[indene-l ,4'- piperidine]-3-yl)acetate;
(±)-2-(r-((2-adamantyl)carbamoyl)-7-cMoro-2,3-dihydrospiro[indene-l,4l- piperidine]-3-yl)acetic acid;
(±)-ethyl 2-(l '-((2-adamantyl)carbamoyl)-6-chloro-2.3-dihydrospiro[indene-l ,4'- piperidine]-3-yl)acetate; (±)-2-(r-((2-adamantyl)carbamoyl)-6-chloro-2,3-dihydrospiro[indene-l:,4'- piperidine]-3-yl)acetic acid;
(±)-ethyl 2-(r-((2-adamantyl)carbamoyl)-5-chloro-2,3-dihydrospiro[indene-l,4'- piperidine] -3 -y 1) acetate;
(±)-2-(l'-((2-adamantyl)carbamoyl)-5-chloro-23-dihydrospiro[indene-lJ4'- piperidine]-3-yl)acetic acid;
(±)-2-(r-((2-adamantyl)carbamoyl)-6-methyl-2,3-dihydrospiro[indene-l,4'- piperidine]-3-yl)acetic acid;
(±)-2-(r-((2-adamantyl)carbamoyl)-5-methyl-253-dihydrospiro[indene-l54'- piperidine]-3-yl)acetic acid; (±)-2-( 1 '-((2-adamantyl)carbamoyl)-6-methoxy-2,3 -dihydrospiro [indene- 1,4'- piperidine]-3-yl)acetic acid;
(±)-2-(r-((2-adamantyl)carbamoyl)-6-fluoro-2,3-dihydrospiro[indene-l54'- piperidine] -3 -yl) acetic acid;
(±)-ethyl 2-(7-bromo-r-((l-adamantyl)carbamoyl)-253-dihydrospiro[indene-l54'- piperidine]-3-yl)acetate;
(±)-2-(7-bromo- 1 '-((1 -adamantyl)carbamoyl)-2,3-dihydrospiro[indene-l ,4'- piperidine]-3-yl)acetic acid; (±)-2-(7-bromo- 1 '-((2-adamantyloxy)carbonyl)-2,3-dihydrospiro [indene- 1 ,4'- piperidine]-3-yl)acetic acid;
2-(7-bromo-l'-((2-adaman1yloxy)carbonyl)-2,3-dihydrospiro[indene-l.4'- piperidine]-3-yl)acetic acid, isomer 1 ; lv" 2-(7-bromo- 1 '-((2-adamantyloxy)carbonyl)-2,3 -dihydrospiro [indene- 1 ,4'- piperidine]-3-yl)acetic acid, isomer 2;
(±)-2-(6-methyl-r-((2-adamantyloxy)carbonyl)-2,3-dihydrospiro[indene-l54'- piperidine]-3-yl)acetic acid;
(±)-2-(5-methyl-r-((2-adamantyloxy)carbonyl)-2,3-dihydrospiro[indene-l:i4'- piperidine]-3-yl)acetic acid;
2-(7-bromo-r-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-l,4'- piperidine]-3-yl)propanoic acid;
(±)-ethyl 2-(7-bromo-l '-((2-adamantyl)carbaπ)oyl)-2.3-dihydrospiro[indene-l ,4'- piperidine]-3-yl)-2-methylpropanoate; (±)-2-(7-bromo-r-((2-adamantyl)carbamoyl)-2.3-dihydrospiro[indene-l ,4'- piperidine]-3-yl)-2-methylpropanoic acid;
(±)-2-adamantyl 7-bromo-3-(2-(methylsulfonamido)-2-oxoethyl)-2,3- dihydrospiro[indene-l ,4'-piperidine]-l '-carboxylate;
(±)-7-bromo-N-(2-adaman.tyl)-3-(2-(methylsulfonamido)-2-oxoethyl)-253- dihydrospiro[indene-l ,4'-piperidine]-r-carboxamide;
(±)-2-adamantyl 3-(2-(dimethylamino)-2-oxoethyl)-2,3-dihydrospiro [indene- 1 ,4'- piperidine]-r-carboxylate;
2-( 1 '-((1 -carbamoyl-4adamantyloxy)carbonyl)-2 ,3 -dihydrospiro [indene- 1 ,4'- piperidine]-3-yl)acetic acid; 2-(7-bromo-r-(l-fluoro-4-adamantylcarbamoyl)-2J3-dihydrospiro[indene-l,4'- piperidine]-3-yl)acetic acid;
2-(7-bromo-l '-(1 -fluoro-4-adamantylcarbamoyl)-2.3-dihydrospiro[indene- 1 ,4'- piperidine]-3-yl)acetic acid, isomer 1 ;
2-(7-bromo-r-(l-fluoro-4-adamantylcarbamoyl)-2:,3-dihydrospiro[indeπe-l,4'- piperidine]-3-yl)acetic acid, isomer 2;
2-(7-bromo-r-(l-fluoro-4-adamantylcarbamoyl)-2,3-dihydrospiro[indene-l,4'- piperidine]-3-yl)acetic acid, isomer 3; 2-(7-bromo-l '-(1 -hydroxy-4-adamantylcarbamoyl)-253-dihydrospiro[indene- 1 ,4'- piperidine]-3-yl)acetic acid;
2-(7-bromo- 1 '-(1 -hydroxy-4-adamantylcarbamoyl)-2,3-dihydrospiro[indene- 1 ,4'- piperidine]-3-yl)acetic acid, isomer 1; 2-(7-bromo- 1 '-(1 -hydroxy-4-adamantylcarbamoyl)-2 ,3-dihydrospiro[indene- 1 ,4'- piperidine]-3-yl)acetic acid, isomer 2;
2-(7-bromo-r-(l-hydroxy-4-adamantylcarbamoyl)-2,3-dihydrospiro[indene-l,4'- piperidine]-3-yl)acetic acid, isomer 3;
(±)-2-(7-bromo-r-(l,7-dihydroxy-4-adamantylcarbaπioyl)-2,3- dihydrospiro [indene- 1 ,4'-piperidine]-3 -yl)acetic acid;
N-(2-adamantyl)-6-methoxy-3,4-dihydro-2H-spiro[isoquinoline-l :>4'-piperidine]- l'-carboxamide;
N-(2-adamantyl)-3,4-dihydro-2H-spiro[naphthalene- 1 ,4'-piperidine]- 1 '- carboxamide; (2-adamantyI) 9-(2-methoxy-2-oxoethyl)-3-azaspiro[5.5]undecane-3-carboxylate;
2-(3-((2-adamantyI)oxycarbonyl)-3-azaspiro[5.5]undecan-9-yl)acetic acid; methyl 2-(3-((2-adamantyl)carbamoyl)-3-azaspiro[5.5]undecan-9-yl)acetate;
2-(3-((2-adamantyl)carbamoyl)-3-azaspiro[5.5]undecan-9-yl)acetic acid;
N-(2-adamantyl)-3H-spiro [isobenzofuran- 1 ,4'-piperidine] - 1 ' -carboxamide; 2-adamantyl 3H-spiro[isobenzofuran-l,4'-piperidine]-r-carboxylate;
1-tert-butyl r-(trans-l-carbamoyl-4-adamantyl)spiro[indoline-3,4'-piperidine]- 1 , 1 '-dicarboxylate;
N-(2-adamantyl)-2-methylspiro[isoindoline-l,4'-piperdine]-r-carboxamide;
N-(2-adamantyl)spiro [isoindoline- 1 ,4 ' -piperidinε] - 1 ' -carboxami de ; 7-Chloro-N-(2-adamantyl)-2-methylspiro [isoindoline- 1,4' -piperidine]- 1 ' - carboxamide;
2-(r-((l-(benzylcarbamoyl)-4-adamantyloxy)carbonyl)-2,3-dihydrospiro[indene- 1 ,4'-piperidine]-3-yl)acetic acid;
(±)-3-(2-amino-2-oxoethyl)-N-(2-adamantyl)-2,3-dihydrospiro[indene-l,4'- piperidine] -1 '-carboxamide;
1-tert-butyl 1 '-(2-adamantyl)spiro[indolϊne-3,4'-piperidme]-l,r-dicarboxylate;
1-tert-butyl- r-(2-adamantyl) 5-fluorospiro[indoline-3.4'-piperidine]-l.r- dicarboxylate; 1 -tert-butyl- 1 '-(2-adamantyl) 5 -methylspiro [indoline-3 ,4'-piperidine] -1,1'- dicarboxylate;
(±)-3-(2-amino-2-oxoethyl)-7-bromo-N-(2-adamantyl)-2,3-dihydrospiro[indene- 1 ,4'-piperidine]- 1 '-carboxamide;
N-(2-adamantyl)- 1 -oxo- 1.3-dihydrospiro[indene-253'-piperidine]- 1 '-carboxamide;
N-(2-adamantyl)- 1 -hydroxy- 1 ,3-dihydrospiro[indene-2,3 '-piperidine]- 1 '- carboxamide;
N-(2-adamantyl)-2-methyl-3-thioxospiro[isoindoline-ls4'-piperidine]-r- carboxamide;
N-(2-adamantyl)-3-thioxospiro[isoindoline- 1 ,4'-piperidine]- 1 '-carboxamide:
7-chloro-N-(2-adamantyl)-2-methyl-3-thioxospiro[isoindoline-l,4'-piperidin.e]-r- carboxamide;
7-chloro-N-(2-adamantyl)-2-(4-methoxybenzyl)-3-thioxospiro[isoindoline-l,4'- piperidine]-l '-carboxamide; and
7-chloro-N-(2-adamantyl)-2-methyl-3-thioxospiro[isoindolme-l,4'-piperidine]-r- carboxamide; or an enantiomer, diastereomer, geometrieal isomer or pharmaceutically acceptable salt thereof.
Additional compounds of the invention are those of Formula Ia:
Figure imgf000021_0001
wherein:
M and X are C or N; the bonds in the ring containing M and X are single or double bonds provided no consecutive double bonds occur between the member atoms of the ring; n= 0, or 1: s = l; t = 1 or 2;
R1 - R5 are independently hydrogen, COOR6, CH2COOR6, CON(R6)2, CH2CON(R6)2. COR6, SO2R6, CONHSO2R6, CH2CONHSO2R6, alkyl, cycloalkyl, heteroaryl, aryl or arylalkyl wherein the cycloalkyl, heteroaryl, aryl or arylalkyl groups represented by R'-R^ are optionally and independently substituted with 1-3 groups independently selected from the group consisting of halogen, cyano, (Ci-Cό)alkyl, halo(C1-C6)alkyl, CONH2 and NR6SO2R6, except that any one or more of R1 - R5 is absent where the atom to which such R1 - R5 group would otherwise be connected is (i) O5 or (ii) an N that is connected by a double bond to an adjacent atom;
R6 is hydrogen, (Ci-Cio) alkyl, aryl or arylalkyl;
Q is O or NR6; and
R7 is a saturated C7-Cj2 bicycloalkyl or saturated C9-C12 tricycloalkyl in which 1- 2 carbon atoms are optionally replaced with heteroatoms independently selected from N and O5 and which is optionally substituted with 1 -3 substituents independently selected from the group consisting of R6, heteroaryl, oxo-substituted heteroaryl. amino- substituted heteroaryl, heterocyclyl, oxo-substituted heterocyclyl, halogen, hydroxy, hydroxymethyl, C(NOH)NH2, CONHR6, CH2CONHR6- CON(R6)2, CH2CON(R6)2, SO2NHR6, SO2N(R6)2, CO2R6, CH2CO2R6. SO2R6.. NHCOR6, NR6COR6, NHCO2R6, NR6CO2R6, NHSO2R6, and NR6SO2R6; or an enantiomer, diastereomer, geometrical isomer or pharmaceutically acceptable salt thereof.
Preferred compounds of the invention are those of Formula Ia where Q is NR6 or O, R6 is H and/or R7 is 2-adamantyl, l-hydroxy-4-adamantyl, l-hydroxymethyl-4- adamantyl, 1 -carbamoyl-4-adamantyl, l-bicyclo[2.2.2]octyl, 1 -carbamoyl -4- bicyclo[2.2.2]octyl. 9-bicyclo[3.3.1]nonyl or 3-carbamoyl-9-bicyclo[3.3.1]nonyl, and the remainder of the variables are defined above.
Preferred compounds of the invention are those of Formula Ia where none of K, L, M, X, and Y is a basic N, and the remainder of the variables are defined above.
Additional compounds of the invention are those according to Formula Ia':
Figure imgf000023_0001
wherein:
M and X are C or N; the bonds in the ring containing M and X are single or double bonds provided no consecutive double bonds occur between the member atoms of the ring; n= 0, or 1 ; s = l ; t = 1 or 2;
R1 - R5 are independently hydrogen, A-(5-tetrazolyl), A-(cycloalkyl), A-(heteroaryl), A-(heterocyclyl), A-(aryl), A-COOR6, A-CON(R6)2, A-COR6, A-SO2R6, A-CONHSO2R6, A-CONHSO2OR6, A-CONHS O2N(R6)2, A-G=NT, alkyl, alkenyl, cycloalkyl, heteroaryl, heterocyclyl, aryl or arylalkyl, wherein the alkyl, alkenyl, cycloalkyl, heteroaryl, heterocyclyl, aryl, A-(cycloalkyl), A-(heteroaryl), A-(heterocyclyl), A-(aryl) or arylalkyl groups represented by R1 - R5 are optionally and independently substituted with 1 -3 groups independently selected from the group consisting of halogen, hydroxy, cyano, -N(R6)2, -NR6C(O)N(R6)2, -NR6C(O)R6, (C1- C6)alkyl, halo(CrC6)alkyl, (C3-C6)alkoxy, halo(CrC6)alkoxy, CONH2, -SO2R6, -NR6SO2R6, -NR6SO2N(R6)2 and -NR6SO2OR6; when K, L5 M, X, or Y is (-O-) or (-N=), then pi, p2, p3, p4 or p5, respectively, is O: when K, L, M, X, or Y is (-N-), (-C=), or (-CH-), then p 15 p2, p3, p4 or p5, respectively, is 1; when K, L, M, X or Y is (-C-), then pi, ρ2, p3, p4 or p5, respectively, is 2; and when K, L, M, X, or Y is (-C-), and R1, R2, R3, R4 or R5 is connected through a double bond to K, L, M, X or Y, respectively, then pi, p2, p3, p4 or p5, respectively, is l ; A is a single bond, (Ci-C6)alkylene, (Cj-C6)alkenylene, (C]-
C5)alkylCH=.C(0)(C0-C3)alkyl(C3-C6)cycloalkyl(Co-C3)alkylene. C(O)(Ci-C6)alkylene, C(O)(C2-C6)alkenylene, S(O)2(Ci-C6)alkylene, S(O)2(C2-C6)alkenylene, or S(O)2(C0- C3)alkyl(C3-C6)cycloalkyl(Co-C3)alkylene3 each optionally substituted with up to 4 groups, R6:
R6 is hydrogen, (Ci-Cio)alkyl, halo(C]-Ci0)alkyl, hydroxy(C,-C]0)alkyl5 (R6)2N(Ci-Cio)alkyl, aryl or arylalkyl, wherein the aryl and arylalkyl groups are optionally substituted with up to three groups independently selected from halogen, hydroxy, cyano, -N(R6)2, -NR6C(O)N(R6)2, -NR6C(O)R6, (Ci-C6)alkyl, halo(d-C6)alkyl3 (C,-C6)alkoxy, halo(Ci-C6)alkoxy, CON(R6)2, SO2N(R6)2, -SO2R6, -NR6SO2R6, -NR6SO2N(R6)2 and -NR6S02OR6;or
N(R6)2 is a heterocyclyl group containing at least one nitrogen atom, preferably selected from W1 - W7:
-O i I-— N — N ; — N N-R6
W1 W2 W3 W4
Figure imgf000024_0001
W5 W6 W7 Q is O or NR6; and
R7 is a saturated C7-Ci2 bicycloalkyl or saturated C9-Ci2 tricycloalkyl in which 1- 2 carbon atoms are optionally replaced with heteroatoms independently selected from N and O5 and which is optionally substituted with 1 -3 substituents independently selected from the group consisting of R6, heteroaryl, ox o- substituted heteroaryl, amino- substituted heteroaryl, heterocyclyl, oxo-substituted heterocyclyl, halogen, hydroxy, hydroxy(CI-C6)alkyl, C(NOH)NH2, CONHR6, CH2CONHR6, CON(R6)2, CH2CON(R6)2, SO2NHR6, SO2N(R6)2, CO2R6, CH2CO2R6, SO2R6, NHCOR6, NR6COR6, NHCO2R6, NR6CO2R6, NHSO2R6, and NR6SO2R6; or an enantiomer, diastereomer, geometrical isomer or pharmaceutically acceptable salt thereof. Other particular compounds of the invention are according to Formula Ib:
Figure imgf000025_0001
wherein:
X and K are C, N or O; s = l; t = 1 or 2; u = 0, I5 2 or 3;
R8 is independently selected from halogen, cyano, (C]-C6)alkyl3 halo(d-C6)alkyl, (C,-C6)alkoxy5 halo(CrC6)alkoxy, CONH2 and NR6SO2R6; R1 , R4 and R5 is independently H5 COOR6, CH2COOR6, CON(R6)2,
CH2CON(R6)25 COR6, SO2R6, CONHSO2R6, CH2CONHSO2R6. alkyl, cycloalkyl, heteroaryl, aryl or arylalkyl wherein the cyclohexyl, heteroaryl, aryl or arylalkyl groups represented by R1 and R4-R5 are optionally and independently substituted with 1 -3 groups independently selected from the group consisting of halogen, cyano, (C1-C6)alkyl, halo(Ci-C6)alkyl5 CONH2 and NR6SO2R6, except that R4 or R5 is absent where the atom to which such R4 or R5 group would otherwise be connected is (i) O, or (ii) an N that is connected by a double bond to an adjacent atom;
R6 is hydrogen, (Ci-C4)alkyl, aryl or arylalkyl;
Q is O or NR6; and R7 is a saturated C7-C12 bicycloalkyl or saturated C9-C12 tricycloalkyl in which 1-
2 carbon atoms are optionally replaced with heteroatoms independently selected from N and O5 and which is optionally substituted with 1-3 substituents independently selected from the group consisting of R6, heteroaryl, oxo-substituted heteroaryl, amino- substituted heteroaryl. heterocyclyl, oxo-substituted heterocyclyl, halogen, hydroxy, hydroxymethyl, C(NOH)NH2, CONHR6, CH2CONHR6, CON(R6)2, CH2CON(R6)2, SO2NHR6, SO2N(R6)2, CO2R6, CH2CO2R6, SO2R6, NHCOR6, NR6COR6, NHCO2R6, NR6CO2R6, NHSO2R6, and NR6SO2R6, or an enantiomer, diastereomer, geometrical isomer or pharmaceutically acceptable salt thereof.
Preferred compounds of the invention are those of Formula Ib where Q is NR6 or O, R6 is H and/or R7 is 2-adamantyl, l-hydroxy-4-adamantyl, l-hydroxymethyl-4- adamantyl, 1 -carbamoyl-4-adamantyl, l-bicyclo[2.2.2]octyl, 1 -carbamoyl -4- bicyclo[2.2.2]octyl, 9-bicyclo[3.3.1]nonyl or 3-carbamoyl-9-bicyclo[3.3.1]nonyl.
More particular compounds of the invention are those of Formula Ib':
Figure imgf000026_0001
wherein X and K are C, N or O; u = 0, 1, 2 or 3; n= O, or 1 ; s = l; t = 1 or 2;
R1, R4 and RD are independently hydrogen, A-(5-tetrazolyl), A-(cycloalkyl), A-(heteroaryl), A-(heteτocyclyl), A-(aryl), A-COOR6, A-CON(R6)2, A-COR6, A-SO2R6, A-CONHSO2R6, A-CONHSO2OR6, A-CONHS O2N (R6)2, A-CsN, alkyl, alkenyl, cycloalkyl, heteroaryl, heterocyclyl, aryl or arylalkyl, wherein the alkyl, alkenyl, cycloalkyl, heteroaryl. heterocyclyl, aryl, A-(cycloalkyl), A-(heteroaryl), A-(heterocyclyl), A-(aryl) or arylalkyl groups represented by R1 , R4 and R5 are optionally and independently substituted with 1-3 groups independently selected from the group consisting of halogen, hydroxy, cyano, -N(R6)2, -NR6C(O)N(R6)2, -NR6C(O)R6, (C]-C6)alkyl, halo(Ci-C6)alkyl, (Ci-C6)alkoxy, halo(Ci-C6)alkoxy, CONH2, -SO2R6, -NR6SO2R6, -NR6SO2N(R6)2 and -NR6SO2OR6; when K or X is (-0-) or (-N=), then pi or p4, respectively, is 0; when Kor X is (- N-), (-C=), or (-CH-), then pi or p4, respectively, is 1; when K or X is (-C-), then pi or p4, respectively, is 2; and when K or X is (-C-), and R1 or R4 is connected through a double bond to K or X, respectively, then pi or p4, respectively, is 1;
A is a single bond, (Ci-C6)alkylene, (Ci-C6)alkenylene, (Ci-
C5)alkylCH=5C(0)(Co-C3)alkyl(C3-C6)cycloalkyl(Co-C3)alkylene. C(O)(C , -C6)alkylene, C(O)(C2-C6)alkenylene, S(O)2(C1-C6)alkylene, S(O)2(C2-C6)alkenylene, or S(O)2(C0- C3)aIkyl(C3-C6)cycloalkyl(Co-C3)alkylene, each optionally substituted with up to 4 groups, R6;
R4, X, Y and R5 are taken together to form a fused benzene or pyridine ring, which is optionally substituted with 1-3 groups independently selected from the group consisting of halogen, hydroxy, cyano, -N(R6)2, -NR6C(O)N(R6)2, -NR6C(O)R6, (C]- C6)alkyl, halo(C1-C6)alkyl, (C,-C6)alkoxy5 halo(C1-C6)alkoxy, CON(R6)2, SO2N(R6)2, -SO2R6, -NR6SO2R6, -NR6SO2N(R6)2 and -NR6SO2OR6; or
• R6 is hydrogen, (Ci-Cio)alkyl, halo(CrCio)aIkyl, hydroxy (C] -C io)alkyl, (R6)2N(Ci-Cio)alkyl. aryl or arylalkyl, wherein the aryl and arylalkyl groups are optionally substituted with up to three groups independently selected from halogen, hydroxy, cyano, -N(R6)2, -NR6C(O)N(R6)2, -NR6C(O)R6, (C,-C6)alkyl, halo(Ci-C6)alkyl, (Ci-C6)alkoxy, halo(C,-C6)alkoxy, CON(R6)2. SO2N(R6)2, -SO2R6, -NR6SO2R6, -NR6SO2N(R6)2 and -NR6SO2OR6; or
N(R6)2 is a heterocyclyl group containing at least one nitrogen atom, preferably selected from W1 - W7:
I —N^ J I — N J I — N O I — N N-R6
W1 W2 W3 W4
Figure imgf000027_0001
Ws W6 W7
Q is O or NR6; and
R7 is a saturated C7-C12 bicycloalkyl or saturated Cp-Ci2 tricycloalkyl in which 1- 2 carbon atoms are optionally replaced with heteroatoms independently selected from N and O, and which is optionally substituted with 1-3 substituents independently selected from the group consisting of R6, heteroaryl, oxo-substituted heteroaryl, amino- substituted heteroaryl. heterocyclyl, oxo-substituted heterocyclyl, halogen, hydroxy. hydroxy(Ci-C6)alkyl5 C(NOH)NH2, CONHR6. CH2CONHR6, CON(R6)2, CH2CON(R6)2, SO2NHR6, SO2N(R6)2, CO2R6, CH2CO2R6, SO2R6, NHCOR6, NR6COR6, NHCO2R6, NR6CO2R6, NHSO2R6, and NR6SO2R6;
R8 is independently selected from halogen, hydroxy, cyano, -N(R6)2, -NR6C(O)N(R6)2, -NR6C(O)R6, (CrC6)alkyl, halo(Ci-C6)alkyl, (CrC6)alkoxy, halo(C,- C6)alkoxy, CON(R6)2, SO2N(R6)2, -SO2R6, -NR6SO2R6, -NR6SO2N(R6)2 and -NR SO2OR6; or an enantiomer, diastereomer, geometrical isomer or pharmaceutically acceptable salt thereof.
Also preferred are compounds of the invention of Formula Ic:
Figure imgf000028_0001
wherein:
M, X and Y are independently C, N or O, provided that at least one of them is carbon and that when M, X, or Y is O3 any adjacent member atom of the ring cannot be O; the bonds between M and X and between X and Y are single or double bonds but are not both simultaneously double bonds; n = O, 1 or 2; s = l; t = 1 or 2; u = 0, 1 , 2 or 3; R8 is independently selected from halogen, cyano, (C1-Cg)BIlCyI5 halo(C]-C6)alkyl5 (C1-C6)OIkOXy, 1IaIo(C1-C6)OIkOXy, CONH2 and NR6SO2R6;
R3, R4 and R5 are independently H5 COOR6, CH2COOR6, CON(R6)2, CH2CON(R6)2, COR6, SO2R6, CONHSO2R6, CH2CONHSO2R6, alkyl, cycloalkyl, heteroaryl, aryl or arylalkyl, wherein the cyclohexyl, heteroaryl, aryl or arylalkyl groups represented by R3 -R3 are optionally and independently substituted with 1-3 groups independently selected from the group consisting of halogen, cyano, (C)-C6)alkyl, halo(Ci-C6)olkyl, CONH2 and NR6SO2R6, except that R4 or R5 is absent where the atom to which such R4 or R5 group would otherwise be connected is (i) O, or (ii) an N that is connected by a double bond to an adjacent atom;
R6 is hydrogen, (Ci-C-Oalkyl, aryl or arylalkyl;
Q is O or NR6; and
R7 is a saturated C7-C12 bicycloalkyl or saturated C9-C12 tiicycloalkyl in which 1- 2 carbon atoms are optionally replaced with heteroatoms independently selected from N and O, and which is optionally substituted with 1 -3 substituents independently selected from the group consisting of R6, heteroaryl, oxo- substituted heteroaryl, amino- substituted heteroaryl, heterocyclyl., oxo-substituted heterocyclyl, halogen, hydroxy, hydroxymethyl, C(NOH)NH2, CONHR6, CH2CONHR6, CON(R6)2, CH2CON(R6)2; SO2NHR6, SO2N(R6)2, CO2R6, CH2CO2R6, SO2R6, NHCOR6, NR6COR6, NHCO2R6, NR6CO2R6, NHSO2R6, and NR6SO2R6; or an enantiomer, diastereomer, geometrical isomer or pharmaceutically acceptable salt thereof.
Preferred compounds of the invention are those of Formula Ic wherein: n = O; X = C or N; Y = C; the bonds between M and X and between X and Y are single bonds; s = 1 and t=2; R4 is H5 COOR6 or CH2COOR6; R5 is H; R6 is hydrogen or (Ci-C4)alkyl: Q is O5 NH or NR6; and/or R7 is 2-adamantyl, 1 -hydroxy-4-adamantyl, 1- hydroxymethyl-4-adamantyl, l-carbamoyl-4-adamantyl, l-bicyclo[2.2.2]octyl, 1- carbamoyl-4-bicyclo[2.2.2]octyl, 9-bicyclo[3.3.1]nonyl or 3-carbamoyl-9- bicyclo[3.3.1]nonyl, and the remaining variables are as defined for Formula Ic.
Also preferred are compounds of Formula Ic where Q is NR6 or O5 R6 is H and/or R7 is 2-adamantyl, 1 -hydroxy-4-adamantyl, l-hydroxymethyl-4-adamantyl or 1- carbamoyl-4-adamantyl, and the remaining variables are as defined for Formula Ic. An additional embodiment of of the invention is a compound of Formula Ic':
Figure imgf000030_0001
wherein M3 X and Y are independently C, N or O, provided that at least one of them is carbon and that when M, X, or Y is O, any adjacent member atom of the ring cannot be O; n= 0, I, or 2; s = 1 or 2; t = 1 or 2; U = O3 I5 2 or 3;
R3 - R5 are independently hydrogen, A-(5-tetrazolyl), A-(cycloalkyl), A-(heteroaryl), A-(heterocyclyl), A-(aryl), A-COOR6, A-CON(R6)2, A-COR6, A-SO2R6, A-CONHSO2R6, A-CONHSO2OR6,. A-CONHSO2N(R6)2, A-Cs(N, alkyl, alkenyL cycloalkyl, heteroaryl, heterocyclyl, aryl or arylalkyl, wherein the alkyl, alkenyl, cycloalkyl, heteroaryl, heterocyclyl, aryl, A-(cycloalkyl), A-(heteroaryl)5
A-(heterocyclyl), A-(aryl) or arylalkyl groups represented by R3 - R5 are optionally and independently substituted with 1-3 groups independently selected from the group consisting of halogen, hydroxy, cyano, -N(R6)2, -NR6C(O)N(R6)2, -NR6C(O)R6. (Cr C6)alkyl, halo(C1-C6)alkyl, (CrC6)alkoxy. halo(CrC6)alkoxy5 CONH2, -SO2R6, -NR6SO2R6, -NR6SO2N(R6)2 and -NR6SO2OR6; when M. X5 or Y is (-O-) or (-N=), then p3, p4 or p5, respectively, is O: when M, X, or Y is (-N-), (-C=), or (-CH-), then p3, p4 or p55 respectively, is 1 : when M5 X or Y is (-C-). then p3, p4 or p5, respectively, is 2; and when M, X or Y is (-C-), and R3, R4 or R5 is connected through a double bond to M, X or Y, respectively, then p3, p4 or p5, respectively, is 1 ; A is a single bond, (CrC6)alkylene, (Ci-C6)alkenylene, (Ci-C5)alkylCH=, C(0)(Co-C3)alkyl(C3-C6)cycloalkyl(Co-C3)alkylene, C(0)(C,-C6)alkylene, C(O)(C2- C6)alkenylene, S(O)2(C1 -C6)alkylene, S(O)2(C2-C6)alkenylene, or S(O)2(C0-C3)alkyl(C3- C6)cycloalkyl(Co-C3)alkylene, each optionally substituted with up to 4 groups, R6; R4, X, Y and R5 are taken together to form a fused benzene or pyridine ring, which is optionally substituted with 1-3 groups independently selected from the group consisting of halogen, hydroxy, cyano, -N(R6)2, -NR6C(O)N(R6)2, -NR6C(O)R6, (C,- C6)alkyl, halo(C)-C6)alkyl, (Ci-C6)alkoxy, halo(C,-C6)alkoxy, CON(R6)2, SO2N(R6)2, -SO2R6, -NR6SO2R6, -NR6SO2N(R6)2 and -NR6SO2OR6; R6 is hydrogen, (Ci-Cio)alkyl, halo(CrCio)alkyl, hydroxy(C]-Cio)alkyl,
(R6)2N(Ci-Cio)alkyl5 aryl or arylalkyl, wherein the aryl and arylalkyl groups are optionally substituted with up to three groups independently selected from halogen, hydroxy, cyano. -N(R6)2, -NR6C(O)N(R6)2, -NR6C(O)R6, (C,-C6)alkyl, halo(d-C6)alkyl3 (Ci-C6)alkoxy, halo(C,-C6)alkoxy, CON(R6)2, SO2N(R6)2, -SO2R6, -NR6SO2R6, -NR6SO2N(R6);, and -NR6SO2OR6; or
N(R6)2 is a heterocyclyl group containing at least one nitrogen atom, preferably selected from W1 - W7:
-O i- \ — -tN — N N-R6
W1 W2 W3 W4
Figure imgf000031_0001
W5 W6 W7
Q is O or NR6; R7 is a saturated C7-Cj2 bicycloalkyl or saturated Cg-Cn tricycloalkyl in which 1-
2 carbon atoms are optionally replaced with heteroatoms independently selected from N and O, and which is optionally substituted with 1 -3 substituents independently selected from the group consisting of R6, heteroaryl, oxo-substituted heteroaryl, amino- substituted heteroaryl, heterocyclyl, oxo-substituted heterocyclyl, halogen, hydroxy, hydroxy(C, -C6)alkyL C(=NOH)NH2, CONHR6, CH2CONHR6, CON(R6)2,
CH2CON(R6)2, SO2NHR6, SO2N(R6)2, CO2R6, CH2CO2R6, SO2R6, NHCOR6, NR6COR6, NHCO2R6, NR6CO2R6, NHSO2R6, and NR6SO2R6; and R8 is independently selected from halogen, hydroxy, cyano, -N(R6)2, -NR6C(O)N(R6)2, -NR6C(O)R6, (C,-C6)alkyl, halo(Ci-C6)alkyl, (CrC6)alkoxy, halo(C,- C6)alkoxy, CON(R6)2, SO2N(R6)2, -SO2R6, -NR6SO2R6, -NR6SO2N(R6)2 and -NR6SO2OR6; or an enantiomer, diastereomer, geometrical isomer or pharmaceutically acceptable salt thereof.
Preferred compounds of the invention are those of Formula Ic" wherein: n = O; X = C or N; Y = C; the bonds between M and X and between X and Y are single bonds; s = 1 and t=2; R4 is H, COOR6 or CH2COOR6; R5 is H; R6 is hydrogen or (C,-C4)alkyl; Q is O, NH or NR6; and/or R7 is 2-adamantyl, l-hydroxy-4-adamantyl, 1- hydroxymethyl-4-adamantyl, l-carbamoyl-4-adamantyl, l-bicyclo[2.2.2]octyl5 1- carbamoyl-4-bicyclo[2.2.2]octyl. 9-bicyclo[3.3.1]nonyl or 3 -carbamoyl -9- bicyclo[3.3.1]nonyl, and the remaining variables are as described for Formula Ic'.
Also preferred are compounds of Formula Ic' where Q is NR6 or O5 R6 is H and/or R7 is 2-adamantyl, l-hydroxy-4-adamantyl, 1-hydroxym ethyl -4-adarαantyl or 1- carbamoyl-4-adamantyl, and the remaining variables are as described for Formula Ic'.
Also preferred are compounds of the invention of Formula Id:
Figure imgf000032_0001
wherein:
K and Y are independently C, N or O; s= 1; t= 1 or 2;
R1 and R5 are independently H, COOR6, CH2COOR6, CON(R6)2, CH2CON(R6)2, COR6, SO2R6, CONHSO2R6, CH2CONHSO2R6. alkyl, cycloalkyl, heteroaryl, aryl or arylalkyl, wherein the cycloalkyl, heteroaryl, aryl or arylalkyl groups represented by R1 and R5 are optionally and independently substituted with 1-3 groups independently selected from the group consisting of halogen, cyano, (Ci-C6)alkyl, halo(C]-C6)alkyl, CONH2 and NR6SO2R6, except that R1 or R5 is absent where the atom to which such R1 or R5 group would otherwise be connected is (i) O, or (ii) an N that is connected by a double bond to an adjacent atom;
R6 is hydrogen, (Ci-C-Oalkyl, aryl or arylalkyl; Q is O or NR6; u = 0, 15 2 or 3;
R8 is independently selected from halogen, cyano, (Ci-C6)alkyl, halo(C)-C6)alkyl, (C,-C6)alkoxy, halo(CrC6)alkoxy, CONH2 and NR6SO2R6; and
R7 is a saturated C7-Ci2 bicycloalkyl or saturated Cg-Ci2 tricycloalkyl in which 1- 2 carbon atoms are optionally replaced with heteroatoms independently selected from N and O, and which is optionally substituted with 1-3 substituents independently selected from the group consisting of R6, heteroaryl, oxo-substituted heteroaryl, amino- substituted heteroaryl, heterocyclyl, oxo-substituted heterocyclyl, halogen, hydroxy, hydroxymethyl, C(NOH)NH2, CONHR6, CH2CONHR6. CON(R6)2, CH2CON(R6)2, SO2NHR6, SO2N(R6)2, CO2R6, CH2CO2R6, SO2R6, NHCOR6, NR6COR6, NHCO2R6, NR6CO2R6, NHSO2R6, and NR6SO2R6; or an enantiomer, diastereomer, geometrical isomer or pharmaceutically acceptable salt thereof.
Preferred compounds of the invention are those of Formula Id where Q is NR6 or O; R6 is H; and/or R7 is 2-adamantyl, l-hydroxy-4-adamantyl, 1 -hydroxymethyl-4- adamantyl, 1 -carbamoyl-4-adamantyl, l-bicyclo[2.2.2]octyl, 1 -carbamoyl-4- bicyclo[2.2.2]octyl, 9-bicyclo[3.3.1]nonyl or 3-carbamoyl-9-bicyclo[3.3.1]nonyl.
Further compounds of the invention are those according to Formula Id':
Figure imgf000033_0001
wherein: K and Y are independently C3 N or O; s = i ; t = 1 or 2;
R1 and R5 are independently hydrogen, A-(5-tetrazolyl), A-(cycloalkyl), A-(heteroaryl), A-(heterocyclyl), A-(aryl)5 A-COOR6, A-CON (R6)2, A-COR6, A-SO2R6, . A-CONHSO2R6. A-CONHSO2OR6, A-CONHSO2N(R6)2, A-C≡N, alkyl, alkenyl, cycloalkyl, heteroaryl, heterocyclyl, aryl or arylalkyl, wherein the alkyl, alkenyl, cycloalkyl, heteroaryl, heterocyclyl, aryl, A-(cycloalkyl), A-(heteroaryl), A-(heterocyclyl), A-(aryl) or arylalkyl groups represented by R1 and R5 are optionally0 and independently substituted with 1-3 groups independently selected from the group consisting of halogen, hydroxy, cyano, -N(R6)2, -NR6C(O)N(R6)2, -NR6C(O)R6, (C,- C6)alkyl, halo(Ci-C6)alkyl, (C1-C6)alkoxy, halo(C,-C6)alkoxy. CONH2, -SO2R6, -NR6SO2R6, -NR6SO2N(R6)2 and -NR6SO2OR6; when K or Y is (-O-) or (-N=), then pi or p5, respectively, is O; when K or Y is 5 (-N-), (-C=), or (-CH-), then pi or p5, respectively, is 1 ; when K or Y is (-C-), then pi or p5, respectively, is 2; and when K or Y is (-C-), and R1 or R5 is connected through a double bond to K or Y, respectively, then pi or p5, respectively, is 1;
A is a single bond, (Cj-C6)alkylene, (C1-C6)alkenylene, (Ci-
C5)alkylCH=,C(0)(Co-C3)alkyl(C3-C6)cycloalkyl(Co-C3)alkylene5 C(0)(C,-C6)alkylene,0 C(O)(C2-C6)alkenylene, S(O)2(C, -Q)alkylene, S(O)2(C2-C6)alkenyIene, or S(O)2(C0- C3)alkyl(C3-C6)cycloalkyl(Co-C3)alkylene, each optionally substituted with up to 4 groups, R6;
R6 is hydrogen, (Ci-C10)alkyl, halo(CrCio)alkyl, hydroxy(Ci-Cio)alkyl, (R6)2N(C,-C]o)alkyl, aryl or arylalkyl, wherein the aryl and arylalkyl groups are 5 optionally substituted with up to three groups independently selected from halogen, hydroxy, cyano, -N(R6)2, -NR6C(O)N(R6)2, -NR6C(O)R6, (C,-C6)alkyl, halo(C,-C6)alkyl5 (C,-C6)alkoxy, halo(C,-C6)alkoxy, CON(R6)2, SO2N(R6)2, -SO2R6, -NR6SO2R6, - -NR6SO2N(R6)2 and -NR6SO2OR6; or
N(R6)2 is a heterocyclyl group containing at least one nitrogen atom, preferably O selected from W1 - W7:
Figure imgf000035_0001
W1 W2 W3 W4
Figure imgf000035_0002
Q is O or NR6; and
R7 is a saturated C7-C12 bicycloalkyl or saturated C9-C12 tricycloalkyl in which 1- 2 carbon atoms are optionally replaced with heteroatoms independently selected from N and O. and which is optionally substituted with 1-3 substituents independently selected from the group consisting of R6, heteroaryl, oxo-substituted heteroaryl, amino- substituted heteroaryl, heterocyclyl, oxo-substituted heterocyclyl, halogen, hydroxy, hydroxy(C,-C6)alkyl, C(NOH)NH2, CONHR6, CH2CONHR6, CON(R6)2, CH2CON(R6)2, SO2NHR6, SO2N(R6)23 CO2R6, CH2CO2R6, SO2R6, NHCOR6, NR6COR6, NHCO2R6, NR6CO2R6, NHSO2R6, and NR6SO2R6; u = 0, 1, 2 or 3;
Rs is independently selected from halogen, hydroxy, cyano, -N(R6)2, -NR6C(O)N(R6)2, -NR6C(O)R6, (C,-C6)alkyl, halo(C1-C6)alkyl, (CrC6)alkoxy, halo(C3- C6)alkoxy, CON(R6)2, SO2N(R6)2, -SO2R6, -NR6SO2R6, -NR6SO2N(R6), and -NR6SO2OR6; or an enantiomer, diastereomer, geometrical isomer or pharmaceutically acceptable salt thereof.
Another particular embodiment of the invention are compounds of the formula:
Figure imgf000035_0003
wherein Q is O or NH; and/or R7 is 2-adamantyl, l-hydroxy-4-adamantyl, 1- (hydroxymethyl)-4-adamantyl, or l-carbamoxyl-4-adamantyl; and the rest of the variables are as described for Formula Id"; or an enantiomer, diastereomer, geometical isomer or pharmaceutically acceptable salt thereof.
Also preferred are compounds of the invention of Formula Ie:
Figure imgf000036_0001
wherein R4, R7, Q, s and t are as defined for Formula I* above; u = 0, 1, 2 or 3;
R8 is independently selected from halogen, hydroxy, cyano, -N(R6)2, -NR6C(O)N(R6)2, -NR6C(O)R6, (C,-C6)alkyl, halo(d-C6)alkyl, (C,-C6)alkoxy, halo(C,- C6)alkoxy, CON(R6)2s SO2N(R6)2, -SO2R6, -NR6SO2R6, -NR6SO2N(R6)2 and -NR6SOaOR6; or an enantiomer, diastereomer, geometrical isomer or pharmaceutically acceptable salt thereof.
Preferred compounds of the invention are those of Formula Ie where R4 is hydrogen, A-(5-tetrazolyl), A-COOR6, ACON(R6)2, A-CONHSO2R6 or alkyl, where the alkyl represented by R4 is optionally substituted with 1-3 groups independently selected from the group consisting of hydroxy, cyano, -N (R6)2, -NRδC(O)N(R6)2, -NR6C(O)R6, (C,-C6)alkyl, halo(Ci-C6)alkyl, -CONH2, -SO2R6, -NR6SO2R6, -NR6SO2N(R6)2 and -NR6SO2OR6: A is a bond or
Figure imgf000036_0002
s = 1; t = 2: Q is NH or O: R7 is 2- adamantyl, l-hydroxy-4-adamantyl, 1 -hydroxymethyl-4-adamantyl, 1 -carbamoyl-4- adamantyl, l-(methylsulfonyl)-4-adamantyl, l-(aminosulfonyl)-4-adaraantyl, 1- bicyclo[2.2.2]octyL l-carbamoyl-4-bicyclo[2.2.2]octyl, 9-bicyclo[3.3.1]nonyl or 3- carbamoyl-9-bicyclo[3.3. l]nonyl; u = 1; and/or R8 is halogen or methyl; and the rest of the variables are as defined for Formula I* above. Also preferred are compounds of the invention of Formula If:
Figure imgf000037_0001
wherein R4, R7, Q, s and t are as defined for Formula I above; U = O5 1, 2 or 3; R8 is independently selected from halogen, hydroxy, cyano, -N(R6)?,
-NR6C(O)N(R6)2, -NR6C(O)R6, (Ci-C6)alkyl, halo(C,-C6)alkyl, (Ci-C6)alkoxy; halo(Ci- C6)alkoxy, CON(R6)2, SO2N(R6)2, -SO2R6, -NR6SO2R6, -NR6SO2N(R6)2 and -NR6SO2OR6; or an enantiomer, diastereomer, geometrical isomer or pharmaceutically acceptable salt thereof. Preferred compounds of the invention are those of Formula If wherein R4 is hydrogen, A-COOR6, A-COR6 Or A-SO2R6; A is a single bond, (CrC6)alkylene5 C(O)(C i-C6)alkylene, or S(O)2(C i-C6)alkylene; s = 1 ; t = 2; Q is NH or O; R7 is 2- adamantyl, 1 -hydroxy-4-adamantyl, l-hydroxymethyl-4-adamantyl, l-carbamoyl-4- adamantyl. l-(methylsulfonyl)-4-adamantyl, 1 -(ammosulfonyl)-4-adamantyl, 1- bicyclo[2.2.2]octyl, l-carbamoyl-4-bicyclo[2.2.2]octyl, 9-bicyclo[3.3.1]nonyl or 3- carbamoyl-9-bicyclo[3.3.1]nonyl; u = 1; and/or R8 is halogen or methyl; and the rest of the variables are as defined for Formula I* above. Also preferred are compounds of the invention of Formula Ig:
Figure imgf000038_0001
wherein R4, R5, R7, Q, s and t are as defined for Formula I* above; u = 0, I5 2 or 3;
R8 is independently selected from halogen, hydroxy, cyano, -N(R6)2, -NR6C(O)N(R6)2, -NR6C(O)R6, (C,-C6)alkyl5 halo(CrC6)alkyl, (C,-C6)alkoxy, halo(Ci- C6)alkoxy, CON(R6)2, SO2N(R6)2, -SO2R6, -NR6SO2R6, -NR6SO2N(R6)2 and -NR6SO2OR6; or an enantiomer, diastereomer, geometrical isomer or pharmaceutically acceptable salt thereof.
Preferred compounds of the invention are those of Formula Ig wherein R4 and R5 are independently selected from hydrogen and (Ci-C3)alkyl; s = 1 : t = 2; Q is NH or O: R7 is 2-adamantyl, l-hydroxy-4-adamantyl, 1 -hydroxymethyl-4-adamantyl, 1 - carbamoyl-4-adamantyl, 1 -(methylsulfonyI)-4-adamantyl, 1 -(aminosulfonyl)-4- adamantyl, l-bicyclo[2.2.2]octyl,'l-carbamoyl-4-bicyclo[2.2.2]octyl, 9- bicyclo[3.3.1]nσnyl or 3-carbamoyl-9-bicyclo[3.3.1]nonyl: u — 1; and/or R8 is halogen or methyl; and the rest of the variables are as defined for Formula I* above.
Also preferred are compounds of the invention of Formula Ih:
Figure imgf000038_0002
R7 wherein R > 5, R r> 7 , 5 s and t are as defined for Formula I X*. above; U = O5 1, 2 or 3;
R8 is independently selected from halogen, hydroxy, cyano, -N(R6)2, -NR6C(O)N(R6)2, -NR6C(O)R6, (Ci-C6)alkyl, halo(CrC6)alkyl, (Ci-C6)alkoxy, halo(Ci- C6)alkoxy, CON(R6)2, SO2N(R6)2, -SO2R6, -NR6SO2R6, -NR6SO2N(R6)2 and -NR6SO2OR6; or an enantiomer, diastereomer, geometrical isomer or pharmaceutically acceptable salt thereof.
Preferred compounds of the invention are those of Formula Ih where R5 is hydrogen or (Ci-C3)alkyl; s = 1 ; t = 2; Q is NH or O; R7 is 2-adamantyl, l-hydroxy-4- adamantyl, 1 -hydroxymethyl-4-adamantyl, l-carbamoyl-4-adamantyl, 1- (methylsulfonyl)-4-adamantyl, 1 -(aminosulfonyl)-4-adamantyl, l-bicyclo[2.2.2]octyl, 1- carbamoyl-4-bicyclo[2.2.2]octyl, 9-bicyclo[3.3.1]nonyl or 3-carbamoyl-9- bicyclo[3.3.1]nonyl; u = 1 ; and/or R8 is halogen, methyl or methoxy; and the rest of the variables are as defined for Formula I* above.
Also preferred are compounds of the invention of Formula Ii:
Figure imgf000039_0001
wherein R4, R7, Q, s and t are as defined for Formula I* above; u = 0, 1, 2 or 3;
R8 is independently selected from halogen, hydroxy, cyano, -N(R6)2, -NR6C(O)N(R6)2, -NR6C(O)R6, (Ci-C6)alkyl, haio(Ci-C6)alkyl5 (Ci-C6)alkoxy, halo(Cr C6)alkoxy, CON(R6)2, SO2N(R6)2, -SO2R6, -NR6SO2R6, -NR6SO2N(R6)2 and -NR6SO2OR6; or an enantiomer, diastereomer, geometrical isomer or pharmaceutically acceptable salt thereof.
Preferred compounds of the invention are those of Formula Ii where R4 is A-COOR6, A-CON(R6)2j A-COR6, A-SO2R6, or alkyl; A is a single bond, (C,- C6)alkylene, (d-C6)alkenylene, C(0)(C0-C3)alkylene(C3-C6)cycloalkyl(Co-C3)alkylene3 C(O)(C i-C6)alkylene or S(O)2(C i-C6)alkylene, optionally substituted with up to 2 (C1- C3)alkyl groups, and (ii) R6 and N(R6)2 are as defined for Formula I above; s = 1; t = 2; Q is NH or O; R7 is 2-adamantyl, l-hydroxy-4-adamantyl, l-hydroxymethyl-4-adamantyl, l-carbamoyl-4-adamantyl, 1 -(methylsulfonyl)-4-adamantyl, 1 -(aminosulfonyl)-4- adamantyl. l-bicyclo[2.2.2]octyl, l-carbamoyl-4-bicyclo[2.2.2]octyl, 9- bicyclo[3.3.1]nonyl or 3-carbamoyl-9-bicyclo[3.3.1]noπyl; u = 1; and/or R8 is halogen or methyl; and the rest of the variables are as defined for Formula I* above.
A further embodiment of the present invention is a compound according to formula Ij:
Figure imgf000040_0001
whereiniX1 is :
Figure imgf000040_0002
and X2 is NR10; or X1 is CH2, and X2 is:
Figure imgf000040_0003
u = 0, 1, 2, 3 or 4; R9 is oxo, hydroxy or thioxo; R10 is H, (C1-C6)alkyl, or substituted or uhsubstituted arylalkyl; and R11 is independently selected from halogen, hydroxy, cyano, -N(R6)2, -NR6C(O)N(R6)2, -NR6C(O)R6, (C,-C6)alkyl, halo(CrC6)alkyl. (CrC6)alkoxy, halo(C,-C6)alkoxy, CON(R6)2, SO2N(R6)2, -SO2R6, -NR6SO2R6, -NR6SO2N(R6)2 and -NR6SO2OR6; or a pharmaceutically acceptable salt thereof.
A particular embodiment of Formula Ij is a compound wherein X2 is NR10 and X1 is :
Figure imgf000041_0001
A more particular embodiment of Formula Ij is a compound wherein X and X are defined as in the preceding paragraph, R9 is thioxo and/or R10 is H, methyl or 4- m ethoxybenzy 1.
An additional embodiment of Formula Ij is a compound, wherein X1 is CH2, and X2 is:
Figure imgf000041_0002
A more particular emobodiment of Formula Ij is a compound wherein X :' aanndd X ^2 are defined in the preceding paragraph, R9 is oxo or hydroxy, and/or u is 1 and R11 is halogen. More particularly, in one embodiment, R1 ' is chloro.
A more particular emobodiment of Formula Ij is a compound wherein X1 and X2 are defined in the preceding paragraph, R9 is oxo or hydroxy, and/or u is 0. The present invention further provides a pharmaceutical composition comprising a disclosed 1 lβ-HSDl inhibitor, including a compound of the Formulae I*, I3 Ia, Ia', Ib, Ib', Ic5 Ic', Id, Id', Ie, If, Ig5 Ih, Ii or Ij and a pharmaceutically acceptable carrier.
The present invention further provides a pharmaceutical composition comprising a disclosed 1 lβ-HSDl inhibitor, including a compound of the Formulae I5 Ia, Ib5 Ic5 or Id and a pharmaceutically acceptable carrier.
The present invention further provides methods of modulating 1 lβ-HSDl comprising administering to a mammal in need thereof an effective amount of a disclosed 1 lβ-HSDl inhibitor, including a compound of Formulae I*, I, Ia, Ia', Ib, Ib', Ic5 Ic', Id5 Id', Ie5 If5 Ig, Ih, Ii or Ij.
The present invention further provides methods of modulating 11 β-HSDl by contacting 1 lβ-HSDl with a disclosed 1 lβ-HSDl inhibitor, including a compound of Formulae I, Ia, Ib, Ic5 or Id.
The present invention further provides methods of inhibiting 11 β-HSDl comprising administering to a mammal in need thereof an effective amount of a disclosed 1 lβ-HSDl inhibitor, including a compound of Formulae I, Ia, Ib, Ic or Id.
The present invention further provides methods of inhibiting 1 lβ-HSDl comprising administering to a mammal in need thereof an effective amount of a disclosed 1 lβ-HSDl inhibitor, including a compound of Formulae I*, I, Ia, Ia', Ib5 Ib', Ic, Ic', Id, Id', Ie, If, Ig5 Ih, Ii or Ij.
The present invention further provides methods of inhibiting the conversion of cortisone to Cortisol in a cell comprising administering to a mammal in need thereof an effective amount of a compound of Formulae I, Ia, Ib5 Ic, or Id.
The present invention further provides methods of inhibiting the conversion of cortisone to Cortisol in a cell comprising administering to a mammal in need thereof an effective amount of a disclosed 1 lβ-HSDl inhibitor;, including a compound of Formulae I*, I, Ia, Ia', Ib, Ib', Ic, Ic', Id, Id', Ie, If, Ig, Ih, Ii or Ij.
The present invention further provides methods of inhibiting production of Cortisol in a cell comprising administering to a mammal in need thereof an effective amount of a disclosed 11 β-HSDl inhibitor, including a compound of Formulae I, Ia, Ib, Ic, or Id.
The present invention further provides methods of inhibiting production of Cortisol in a cell comprising administering to a mammal in need thereof an effective amount of a disclosed 1 lβ-HSDl inhibitor, including a compound of Formulae I*, I, Ia3 Ia', Ib, Ib', Ic, Ic', Id3 Id', Ie3 If5 Ig, Ih3 Ii or Ij.
The present invention further provides methods of increasing insulin sensitivity comprising administering to a mammal in need thereof an effective amount of a disclosed 11 β-HSDl inhibitor, including a compound of Formulae I3 Ia, Ib, Ic, or Id.
The present invention further provides methods of increasing insulin sensitivity comprising administering to a mammal in need thereof an effective amount of a disclosed 1 lβ-HSDl inhibitor, including a compound of Formulae I*, I, Ia, Ia', Ib, Ib', Ic3 Ic', Id, Id', Ie, If, Ig3 Ih, Ii or Ij. The present invention further provides methods of treating diseases associated with activity or expression of 11 β-HSDl comprising administering to a mammal in need thereof an effective amount of a disclosed 1 lβ-HSDl inhibitor, including a compound of Formulae I, Ia, Ib, Ic3 or Id.
The present invention further provides methods of treating diseases associated with activity or expression of 11 β-HSDl comprising administering to a mammal in need thereof an effective amount of a disclosed 1 lβ-HSDl inhibitor, including a compound of Formulae I*, I3 Ia, Ia', Ib, Ib', Ic, Ic', Id, Id', Ie, If, Ig3 Ih, Ii or Ij.
Also included in the present invention is the use of a disclosed 11 β-HSDl inhibitor, including a compound of Formulae I*, I3 Ia, Ia', Ib3 Ib', Ic3 Ic', Id, Id% Ie3 If3 Ig, Ih, Ii or Ij or a pharmaceutically acceptable salt thereof for the manufacture of a medicament, wherein the values for the variables are as described above for the pharmaceutical composition of the invention. The medicament is for treating a disease or disorder related to the activity or expression of 1 lβ-HSDl , inhibiting the conversion of cortisone to Cortisol in a cell, inhibiting production of Cortisol in a cell, increasing insulin sensitivity, modulating 11 β-HSDl, and/or inhibiting 1 lβ-HSDl.
Also included in the present invention is the use of a disclosed 1 lβ-HSDl inhibitor, including a compound of Formulae I*, I, Ia, Ia', Ib, Ib', Ic, Ic', Id. Id', Ie3 If3 Ig, Ih, Ii or Ij or a pharmaceutically acceptable salt thereof for therapy, such as treating a disease or disorder related to the activity or expression of 11 β-HSDl, inhibiting the conversion of cortisone to Cortisol in a cell, inhibiting production of Cortisol in a cell, increasing insulin sensitivity, modulating 1 lβ-HSDl, and/or inhibiting 1 lβ-HSDl. Values for the variables of the Formulae are as described above. Also included in the present invention is the use of a disclosed 1 lβ-HSDl inhibitor, including a compound of Formulae I*, I, Ia5 Ia', Ib, Ib', Ic, Ic', Id, Id', Ie, If, Ig, Ih, Ii or Ij or a pharmaceutically acceptable.salt thereof for treating a disease or disorder related to the activity or expression of 1 lβ-HSDl, inhibiting the conversion of cortisone to Cortisol in a cell, inhibiting production of Cortisol in a cell, increasing insulin sensitivity, modulating 1 lβ-HSDl, and/or inhibiting 1 lβ-HSDl . Values for the variables of the Formuale are as described above.
DETAILED DESCRIPTION OF THE INVENTION Definitions:
When any variable (e.g., aryl, heterocyclyl, R1, R2, etc.) occurs more than once in a compound, its definition on each occurrence is independent of any other occurrence.
The term "alkyl" means a straight or branched hydrocarbon radical having 1-10 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-buryl, sec- butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like.
The term "loweralkyl" means a C1-C7 straight or branched alkyl group. "Alkylene" means a saturated aliphatic straight-chain divalent hydrocarbon radical having the specified number of carbon atoms, e.g., -(CHa)x- wherein x is a positive integer such as 1-10, preferably 1-6. Thus, "(Ci-C6)alkylene" means a radical having from 1-6 carbon atoms in a linear or branched arrangement, with optional unsaturation or optional substitution.
The term "cycloalkyl" means a saturated hydrocarbon ring having 3-8 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
The term "bicycloalkyF" means two saturated hydrocarbon rings having a total of 7-12 carbon atoms which are joined by 1,1-fusion, 1,2-fusion or l,n-fusion to give spirocyclic ring systems, fused ring systems and bridged ring systems respectively. Spirocyclic ring systems include, for example, spiro[2.4]heptane, spiro[2.5]octane, spiro[4.4]nonane, spiro[4.5]decane, spiro[5.5]undecane and the like. Fused ring systems include, for example, bicyclo[4.1.0]heptane, octahydro-lH-indene, decahydronaphthalene and the like. Bridged ring systems include for example, bicyclo[3.3.1]nonane, bicyclo[2.2.2]octane, bicyclo[2.2.1]heptane and the like. The term "tricycloalkyl" means three saturated hydrocarbon ring having a total of 9-12 carbon atoms which are joined by any combination of 1,1-fusion, 1,2-fusion or l,n- fusion and includes, for example, adamantyl, noradamantyl and the like.
The terms "alkoxy" and "alkylthio" are O-alkyl or S-alkyl, respectively, of 1-6 carbon atoms as defined above for "alkyl."
The term "aryl" means an aromatic radical which is a phenyl group, a phenylalkyl group, a phenyl group substituted with 1-4 substituents selected from alkyl as defined above, alkoxy as defined above, alkylthio as defined above, halogen, trifluoromethyl, dialkylamino as defined above for alkyl, nitro. cyano, and N,N-dialkyl-substituted amido as defined above for alkyl.
The term "heteroaryl" means a 5- and 6- membered heteroaromatic radical which may optionally be fused to a ring containing 1-4 heteroatoms selected from N, O, and S and includes, for example, a heteroaromatic radical which is 2- or 3-thienyl, 2- or 3- furanyl, 2- or 3- pyrrolyl. 2-,3-, or 4-ρyridinyl, 2-pyrazinyl, 2-, 4-, or 5-pyrimidinyl, 3- or 4-pyridazinyl, lH-indol-6-yl, lH-indol-5-yl, lH-benzimidazol-6-yl, lH-benzimidazol-5- yl, 2-, 4-5 or 5-thiazolyl, 3-, A-, or 5-pyrazolyl, 2-, 4-, or 5-imidazolyl and the like optionally substituted by a substituent selected from alkyl as defined above, halogen, dialkylamino as defined above for alkyl, nitro, cyano. and N,N-dialkylsubstituted amido as defined above for alkyl. The term "heterocyclyl" means a 4-, 5-, 6- and 7-membered saturated or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O, and S3 and include pyrrolidine, piperidine. tetrahydrofuran, tetrahydropyran, tetrahydrothiophene, tetrahydrothiopyran, isoxazolidine, 1,3-dioxolane, 1.3-dithiolane, 1,3-dioxane, 1,4-dioxane, 1.3-dithiane, 1 ,4-dithiane, morpholine, thiomorpholine, thiomorpholkie 1,1-dioxide, tetrahydro-2H-l,2-thia2ine 1,1-dioxide, and isothiazolidine 1,1 -dioxide.
The term "arylalkyl" means an aromatic radical attached to an alkyl radical wherein aryl and alkyl are as defined above, for example, benzyl, phenethyl, and the like.
The term "adamantyl" means an adamantane moiety bonded to another atom via the 1- or 2- position of adamantane.
The term "mammal" as used herein includes all mammals, including, but not limited to, humans. A "carbocyclic group" comprises at least one ring formed entirely by carbon- carbon bonds. Such a group generally has from 1 to 3 fused or pendant rings, preferably one ring or two fused rings. Typically, each ring contains from 3 to 10 ring members, preferably from 5 to 8 ring members. Unless otherwise specified, such a ring may be aromatic or non-aromatic. Representative examples of carbocyclic groups are cycloalkyl groups (e.g., cyclopentane and cyclohexane), cycloalkenes and cycloalkynes, as well as aromatic groups such as phenyl, benzyl, naphthyl, phenoxyl, benzoxyl and phenylethanonyl. Carbon atoms present within a carbocyclic group may. of course, be further bonded to a variety of ring substituents, such as hydrogen, a halogen, cyano, nitro, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 alkoxy, C)-C8 alkylthio, hydroxy, amino, mono or di(C]-C8)alkylamino, (C3-C7)cycloalkyl(Co-C3)alkyL halo(C]-Cs)alkyl, halo(Ci-C8)alkoxy, Ci-C8 alkanoyl, Ci-C8 alkoxycarbonyl, -COOH, -CONH2, mono- or di-(Ci-Cs)alkylcarboxamido, -SO2NH2, and mono or di(C]-Cg)alkylsulfonamido.
A "heterocyclic group" comprises at least one ring in which at least one ring atom is a heteroatom (i.e., N, O or S), and the remainder of the ring atoms are carbon.
Preferably, a heterocyclic group comprises 1 -4 heteroatoms; within certain embodiments 1 or 2 heteroatoms is preferred. A heterocyclic group generally has from 1 to 3 fused or pendant rings, preferably one ring or two fused rings. Typically, each ring contains from 3 to 10 ring members, preferably from 5 to 8 ring members, and may be optionally substituted with from 1 to 5 substituents such as halogen, cyano, nitro, Ci-C8 alkyl, C2- Cg alkenyl. C2-C8 alkynyl, Ci-Cg alkoxy, Ci-C8 alkylthio, hydroxy, amino, mono or di(Ci-C8)alkyl amino, halo(C]-C8)alkyl, halo(Ci-C8)alkoxy, hydroxy(CrC8)alkyl, hydroxy(Ci-C8)alkoxy, C2-C8 alkanoyl, Ci-C8 alkoxycarbonyl, -COOH, -SO2NH2, mono or dialkylsulfonamido, -C(O)NH2 or mono or di(C]-C8)alkylcarboxamido. Unless otherwise specified, a heterocyclic group may be aromatic or nonaromatic. As with a carbocyclic group, atoms within a heterocyclic ring may be further linked to a variety of ring substituents.
A heterocyclic ring may be attached to a pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. A nitrogen in the heterocycle may optionally be quaternized. Preferably, if the total number of S and O atoms in the heterocycle exceeds I5 then these heteroatoms are not adjacent to one another. More preferably, the total number of S and O atoms in the heterocycle is not more than 1.
Examples of heterocyclic groups include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothio-furanyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, dithiazϊnyl, dihydrofurotetrahydrofuran, fiiranyl, furazanyl, imidazolidinyl, imidazoliπyl, imidazolyl, indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyL pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, thiadiazinyl, thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl and xanthenyl. It will be apparent that any such heterocyclic groups may be substituted with one or more substituents as described above. Preferred heterocyclic groups include, for example, pyridyl, pyrimidinyl (e.g., pyrimidin-2-yl), pyridinyl (pyridin-2-yl, pyridin-3-yl and pyridin-4-yl), morpholinyl (e.g., morpholin-4-yl), piperidinyl (e.g., piperidin-1-yl), pyrrolidinyl (e.g., pyrrolidin-1- yl), tetrazolyl, triazinyl, thienyl, coumarinyl. imidazolyl, oxazolyl, isoxazolyl, indolyl, pyrrolyl, pyrazolyl, quinolinyl, isoquinolinyl, thiazolyl, benzothiadiazolyl, triazolyl, pyrazinyl, furyl, thienyl, benzothienyl, benzofuranyl, tetrahydropyranyl, tetrahydrofuranyl. indanyl, and substituted derivatives of the foregoing such as methyl- tetrahydropyran-2-yl and 2-hydroxy-indan-l-yl.
The term "halogen" means fluorine, chlorine, iodine or bromine.
The term "basic nitrogen" refers to a nitrogen atom that is >50% protonated in aqueous solution at pH 7 and includes, for example, the nitrogen atoms dialkylamines and trialkylamines.
Compounds of Formulae I*, I, Ia, Ia', Ib, Ib', Ic, Ic', Id, Id', Ie, If, Ig, Ih, and Ii may exist in various stereoisomeric or tautomeric forms. The invention encompasses all such forms, including active compounds in the form of essentially pure enantiomers, racemic mixtures, and tautomers, including forms those not depicted structurally.
The compounds of the invention may be present in the form of pharmaceutically acceptable salts. For use in medicines, the salts of the compounds of the invention refer to non-toxic "pharmaceutically acceptable salts." Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/cationic salts.
Pharmaceutically acceptable acidic/anionic salts include, the acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide; calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate, glutamate, glycoUylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malatef maleate, mandelate, mesylate, methylsulfate. mucate, napsylate, nitrate, pamoate, pantothenate, phosphate/diphospate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate, and triethiodide salts.
The compounds of the invention include pharmaceutically acceptable anionic salt forms, wherein the anionic salts include the acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate. iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate/diphospate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate. tosylate, and triethiodide salts. When a disclosed compound or its pharmaceutically acceptable salt is named or depicted by structure, it is to be understood that solvates or hydrates of the compound or its pharmaceutically acceptable salts are also included. "Solvates" refer to crystalline forms wherein solvent molecules are incorporated into the crystal lattice during crystallization. Solvate may include water or nonaqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and EtOAc. Solvates, wherein water is the solvent molecule incorporated into the crystal lattice, are typically referred to as "hydrates". Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water.
When a disclosed compound or its pharmaceutically acceptable salt is named or depicted by structure, it is to be understood that the compound, including solvates thereof, may exist in crystalline forms, non-crystalline forms or a mixture thereof. The compound or its pharmaceutically acceptable salts or solvates may also exhibit polymorphism (i.e. the capacity to occur in different crystalline forms). These different crystalline forms are typically known as "polymorphs." It is to be understood that when named or depicted by structure, the disclosed compound and its pharmaceutically acceptable salts, solvates or hydrates also include all polymorphs thereof. Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification. One of ordinary skill in the art will appreciate that different polymorphs may be produced, for example, by changing or adjusting the conditions used in solidifying the compound. For example, changes in temperature, pressure, or solvent may result in different polymorphs. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions.
The invention also includes various isomers and mixtures thereof. "Isomer" refers to compounds that have the same composition and molecular weight but differ in physical and/or chemical properties. The structural difference may be in constitution (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers).
Certain of the disclosed aspartic protease inhibitors may exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. Enantiomers are pairs of stereoisomers whose mirror images are not superimposable, most commonly because they contain an asymmetrically substituted carbon atom that acts as a chiral center. "Enantiomer" means one of a pair of molecules that are mirror images of each other and are not superimposable. Diastereomers are stereoisomers that are not related as mirror images, most commonly because they contain two or more asymmetrically substituted carbon atoms. The symbol "*" in a structural formula represents the presence of a chiral carbon center, "i?" and "5" represent the configuration of substituents around one or more chiral carbon atoms. Thus, "R*" and "<S*" denote the relative configurations of substituents around one or more chiral carbon atoms. When a chiral center is not defined as R or S, a mixture of both configurations is present.
"Racemate" or "racemic mixture" means a compound of equimolar quantities of two enantiomers, wherein such mixtures exhibit no optical activity; i.e., they do not rotate the plane of polarized light.
"Geometric isomer" means isomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a cycloalkyl ring, or to a bridged bicyclic system. Atoms (other than H) on each side of a carbon-carbon double bond may be in an E (substituents are on opposite sides of the carbon-carbon double bond) or Z (substituents are oriented on the same side) configuration.
The compounds of the invention may be prepared as individual isomers by either isomer-specific synthesis or resolved from an isomeric mixture. Conventional resolution techniques include forming the salt of a free base of each isomer of an isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each isomer of an isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each of the isomers of an isomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving an isomeric mixture of either a starting material or a final product using various well known chromatographic methods. When a disclosed compound is named or depicted by structure without indicating the stereochemistry, and the compound has at least one chiral center, it is to be understood that the name or structure encompasses one enantiomer of inhibitor free from the corresponding optical isomer, a racemic mixture of the inhibitor and mixtures enriched in one enantiomer relative to its corresponding optical isomer. A pharmaceutical composition of the invention may, alternatively or in addition to a compound of Formulae I*. I3 Ia, Ia', Ib, Ib', Ic, Ic', Id, Id'. Ie5 If. Ig, Ih5 Ii or Ij, comprise a pharmaceutically acceptable salt of a compound of Formulae 1*, I5 Ia, Ia% Ib, Ib', Ic, Ic' , Id3 Id', Ie3 If3 Ig3 Ih3 Ii or Ij3 or a prodrug or pharmaceutically active metabolite of such a compound or salt and one or more pharmaceutically acceptable carriers therefor. "Prodrug" means a pharmaceutically acceptable form of an effective derivative of a compound (or a salt thereof) of the invention, wherein the prodrug may be: 1) a relatively active precursor which converts in vivo to a compound of the invention; 2) a relatively inactive precursor which converts in vivo to a compound of the invention; or 3) a relatively less active component of the compound that contributes to therapeutic activity after becoming available in vivo (i.e., as a metabolite). See "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985. "Metabolite" means a pharmaceutically acceptable form of a metabolic derivative of a compound (or a salt thereof) of the invention, wherein the derivative is an active compound that contributes to therapeutic activity after becoming available in vivo.
"Effective amount" means that amount of active compound agent that elicits the desired biological response in a subject. Such response includes alleviation of the symptoms of the disease or disorder being treated. The effective amount of a compound of the invention in such a therapeutic method is from about 10 mg/kg/day to about 0.01 mg/kg/day, preferably from about 0.5 mg/kg/day to 5 mg/kg/day.
"Inhibiting 1 Iβ-HSDI" means to decrease the activity of the 1 lβ-HSDl enzyme. "Modulating 11 β-HSD 1 " means to impact the activity of the 11 β-HSD 1 enzyme by altering its natural activity. Modulation can be analogous to inhibition when a disease or disorder relating to the activity 11 β-HSD 1 would be effectively treated by suppressing the activity of the enzyme.
"Pharmaceutically acceptable carrier" means compounds and compositions that are of sufficient purity and quality for use in the formulation of a composition of the invention and that, when appropriately administered to an animal or human, do not produce an adverse reaction.
"Treatment'* or "treating", as used herein, refers to partially or totally inhibiting, delaying, or reducing the severity of the disease or disorder related to 11 β-HSD 1. The terms "treatment" and "treating" also encompass the prophylactic administration of a compound of the invention to a subject susceptible to a disease or disorder related to the activity or expression of 1 lβ-HSDl in an effort to reduce the likelihood of a subject developing the disease or disorder, or slowing or preventing progression of the disease. Prophylactic treatment includes suppression (partially or completely) of the disease or disorder, and further includes reducing the severity of the disease or disorder, if onset occurs. Prophylactic treatment is particularly advantageous for administration to mammals at risk for developing a disease or disorder related to 11 β-HSDl .
The compounds of the present invention can be prepared and administered in a wide variety of oral and parenteral. dosage forms. Thus, the compounds of the present invention can be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally. Additionally, the compounds of the present invention can be administered intranasally or transdermally.
It will be obvious to those skilled in the art that the following dosage forms may comprise as the active ingredient, either compounds or a corresponding pharmaceutically acceptable salt of a compound of the present invention.
For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can either be solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersable granules. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active ingredient.
In tablets, the active ingredient is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from about one to about seventy percent of the active ingredient. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcelluose, a low melting wax, cocoa butter, and the like. Tablets, powders, cachets, lozenges, fast-melt strips, capsules and pills can be used as solid dosage forms containing the active ingredient suitable for oral administration. For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active ingredient is dispersed homogeneously therein, as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
Liquid form preparations include solutions, suspensions, retention enemas, and emulsions, for example, water or water propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
Aqueous solutions suitable for oral administration can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, stabilizing , and thickening agents as desired. Aqueous suspensions for oral administration can be prepared by dispersing the finely divided active ingredient in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethyl cellulose, and other well-known suspending agents.
The pharmaceutical composition is preferably in unit dosage form. In such form, the composition is subdivided into unit doses containing appropriate quantities of the active ingredient. The unit dosage form can be a packaged preparation, the package containing discrete quantities of, for example, tablets, powders, and capsules in vials or ampules. Also, the unit dosage form can be a tablet, cachet, capsule, or lozenge itself, or it can be the appropriate amount of any of these in packaged form.
The quantity of active ingredient in a unit dose preparation may be varied or adjusted from about 0.1 mg to about 1000.0 mg, preferably from about 0.1 mg to about 100 mg. The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill in the art. Also, the pharmaceutical composition may contain, if desired, other compatible therapeutic agents.
In therapeutic treatment or as a method-of-use as an inhibitor of 1 lβ-HSDl or an inhibitor in the production of Cortisol in the cell, the active ingredient is preferably administered orally in a solid dosage form as disclosed above in an amount of about 0.1 mg to about 100 mg per daily dose where the dose is administered once or more than once daily.
The compounds of the invention are useful for ameliorating or treating disorders or diseases in which decreasing the level of Cortisol is effective in treating a disease state. Thus, the compounds of the invention can be used in the treatment or prevention of diabetes mellitus, obesity, metabolic syndrome, insulin resistance, cardiovascular disease, dyslipidemia, atherosclerosis, lipodystrophy, osteoporosis, glaucoma, Cushing's syndrome, depression, anxiety and Alzheimer's disease, cognitive decline (including age-related cognitive decline), polycystic ovarian syndrome and infertility. In addition, . compounds modulate the function of B and T cells of the immune system.
A pharmaceutical composition of the invention may, alternatively or in addition to a compound of Formulae I*, I, Ia, Ia', Ib? Ib', Ic, Ic', Id, Id', Ie, If, Ig, Ih, Ii or Ij, comprise a pharmaceutically acceptable salt of a compound of Formulae I*, I, Ia, Ia', Ib, Ib', Ic5 Ic', Id, Id', Ie, If, Ig, Ih, Ii or Ij, or a prodrug or pharmaceutically active metabolite of such a compound or salt and one or more pharmaceutically acceptable carriers therefor.
The pharmaceutical compositions of the invention are 1 lβ-HSDl inhibitors. Said compositions contain compounds having a mean inhibition constant (IC5o) against 11 β- HSDl of between about 1,000 nM to about 0.001 nM; preferably between about 50 nM to about 0.001 nM; and more preferably between about 5 nM to about 0.01 nM.
The invention includes a therapeutic method for treating or ameliorating an 1 lβ-HSDl mediated disorder in a subject in need thereof comprising administering to a subject in need thereof an effective amount of a compound of Formulae I*, I, Ia, Ia', Ib, Ib', Ic, Ic', Id, Id', Ie, If, Ig, Ih, Ii or Ij, or the enantiomers, diastereomers, or salts thereof or composition thereof.
The compounds of the invention are useful for ameliorating or treating disorders or diseases in which decreasing the level of Cortisol is effective in treating a disease state. Thus, the compounds of the invention can be used in the treatment or prevention of diabetes mellitus, obesity, symptoms of metabolic syndrome, glucose intolerance, hyperglycemica, hypertension, hyperlipidemia, insulin resistance, cardiovascular disease, dyslipidemia, atherosclerosis, lipodystrophy, osteoporosis, glaucoma, Cushing's syndrome, Addison's Disease, visceral fat obesity associated with glucocorticoid therapy, depression, anxiety, Alzheimer's disease, dementia, cognitive decline (including age-related cognitive decline), polycystic ovarian syndrome and infertility. In addition, the compounds modulate the function of B and T cells of the immune system and can therefore be used to treat diseases such as tuberculosis, leprosy and psoriasis. They can also be used to promote wound healing, particularly in diabetic patients. Additional diseases or disorders that are related to 11 β-HSDl activity include those selected from the group consisting of lipid disorders, hypretriglyceridemia, hypercholesterolemia, low HDL levels, high LDL levels, vascular restenosis, pancreatitis, abdominal obesity, neurodegenerative disease, retinopathy, nephropathy, neuropathy, diabetes, coronary heart disease, stroke, peripheral vascular disease, Gushing' s syndrome, hyperinsulinemia, viral diseases, and Syndrome X.
An embodiment of the invention includes administering an llβ-HSDl inhibiting compound of Formula I or pharmaceutical composition thereof in a combination therapy with one or more additional agents for the treatment of diabetes, dyslipidemia, cardiovascular disease, hypertension, obesity, cancer or glaucoma. Agents for the treatment of diabetes include insulins, such as Humulin® (Eli Lilly), Lantus® (Sanofi Aventis), Novolin (Novo Nordisk), and Exubera® (Pfizer); PPAR gamma agonists, such as Avandia® (rosiglitazone maleate, GSK) and Actos® (pioglitazone hydrochloride, Takeda/EIi Lilly); sulfonylureas, such as Amaryl® (glimepiride, Sanofi Aventis), Diabeta® (glyburide, Sanofi Aventis), Micronase®/Glynase® (glyburide, Pfizer), and Glucotrol®/Glucotrol XL® (glipizide, Pfizer); meglitinides, such as Prandin®/NovoNorm® (repaglinide, Novo Nordisk), Starlix® (nateglinide, Novartis), and Glufast® (mitiglinide, Takeda); biguanides, such as Glucophase®/Glucophase XR® (metformin HCI, Bristol Myers Squibb) and Glumetza (metformin HCl, Depomed); thiazolidinediones; amylin analogs; GLP-I analogs; DPP-IV inhibitors, such as Januvia® (sitagliptin, Merck); PTB-IB inhibitors; protein kinase inhibitors (including AMP- activated protein kinase inhibitors); glucagon antagonists; glycogen synthase kinase-3 beta inhibitors; glucose-6-phosphatase inhibitors; glycogen phosphorylase inhibitors; sodium glucose co-transporter inhibitors, and α-glucosidase inhibitors, such as Precose®/Glucobay®/Prandase®/ Glucor® (acarbose, Bayer) and Glyset® (miglitol, Pfizer). Agents for the treatment of dyslipidemia and cardiovascular disease include statins, fibrates and ezetimϊbe. Agents for the treatment of hypertension include α- blockers, β-blockers, calcium channel blockers, diuretics, angiotensin converting enzyme (ACE) inhibitors, dual ACE and neutral endopeptidase (NEP) inhibitors, angiotensin- receptor blockers (ARBs), aldosterone synthase inhibitor, aldosterone-receptor antagonists, or endothelin receptor antagonist. Agents for the treatment of obesity include orlistat, phentermine, sibutramine and rimonabant. An embodiment of the invention includes administering an llβ-HSDl inhibiting compound of Formula I or composition thereof in a combination therapy with one or more other llβ-HSDl inhibitors (whether such inhibitors are also compounds of Formula I or are compounds of a different class/genus), or with combination products, such as Avandamet® (metformin HCl and rosiglitazone maleate. GSK); Avandaryl® (glimepiride and rosiglitazone maleate, GSK); Metaglip® (glipizide and metformin HCl, Bristol Myers Squibb); Janumet® (sitagliptin and metformin. Merck)and Glucovance® (glyburide and metformin HCl, Bristol Myers Squibb).
The following abbreviations have the indicated meanings:
Abbreviation Meaning
BINAP 2,2'-bis(diphenylphosphino)-l ,1 '-binaphthyl
Boc ferf-butoxy carbonyl or *-butoxy carbonyl
(Boc)2O di-tert-bnty\ dicarbonate
Cbz Benzyloxycarbonyl
CbzCl Benzyl chloroformate
CDI carbonyldiimidazole d day
DAST diethylaminosulfur trifluoride
DBU l,8-diazabicyclo[5.4.0]undec-7-ene
DCC N5N' -dicyclohexylcarbodiimide
DCU N5N' -dicyclohexylurea
DlAD diisopropyl azodicarboxylate
DIBAL, DIBAH diisobutylaluminum hydride
DIEA N,N-diisopropylethylamine
DMAP 4-(dimethylamino)pyridine
DMF N,N-dimethylformamide
DMPU 1 ,3-dimethyl-3 A5,6-tetrahydro-2(] H)-pyrimidinone
2,4-DNP 2,4-dinitrophenylhydrazine
EDCHCl l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride equiv equivalents
EtOAc ethyl acetate
Fmoc l-[[(9H-fluoren-9-ylmethoxy)carbonyl]oxy]- Fmoc-OSu l-[[(9H-fluoren-9-ylmethoxy)carbonyl]oxy]-2,5- pyrrolidinedione
HCl hydrochloric acid
HOBt 1 -hydroxybenzotriazole
HATU 2-(7- Aza- 1 H-benzotriazole- 1 -yl)-l , 1.3.3-tetraniethyluronium hexafluorophosphate
HBTU 2-(lH-Benzotriazole-l -yl)-l , 1 ,3,3-tetramethyluronium hexafluorophosphate
HPLC high pressure-liquid chromatography
KHMDS potassium hexamethyldisilazane
LAH or LiAlH4 lithium aluminum hydride
LC-MS liquid chromatography-mass spectroscopy
LHMDS lithium hexamethyldisilazane
MeCN acetonitrile
MeOH methanol min minute
MS mass spectrum
MsCl methanesulfonyl chloride
NaH sodium hydride
NaHCO3 sodium bicarbonate
NaN3 sodium azide
NaOH sodium hydroxide
Na2SO4 sodium sulfate
NMM N-methylmorpholine
NMP N-methylpyrrolidinone
Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0)
Pd(OAc)2 Palladium(II)Acetate
Pd(OH)2 PalladiumHydroxide
PE petroleum ether
PtO2 Platinum Oxide quant quantitative yield rt room temperature satd saturated
SOCl2 thionyl chloride
SFC supercritical fluid chromatography
SPA scintillation proximity assay <•
SPE solid phase extraction TBS t-butyldimethylsilyl
TBSCl t-butyldimethylsilyl chloride
TEA triethylamine or Et3N
TEMPO 2,2,6,6-tetrarnethyl-l-piperidinyloxy free radical
Teoc l-[2-(trimethylsilyl)ethoxycarbonyloxy]-
Teoc-OSu l-[2-(trimethylsilyl)ethoxycarbonyloxy]pyrrolidin-2,5-dione
TFA trifluoroacetic acid
THF tetrahydrofuran
TLC thin layer chromatography
TMS trimethylsilyl
TMSCl chlorotrimethylsilane or trimethylsilyl chloride retention time
TsOH p-toluenesulfonic acid
GENERAL DESCRIPTION OF SYNTHESIS
Compounds of Formulae I*, I5 Ia, Ib5 Ic, Id5 Ie. If5 Ig, Ih5 Ii and Ij can be prepared by several processes. In the discussion below n, s, t, u, A, K5 L5 M, X, Y, Q and R]-R8a have the meanings indicated above unless otherwise noted. In cases where the synthetic intermediates and final products of Formulae I*, I5 Ia, Ib, Ic, Id5 Ie5 If5 Ig, Ih5 Ii or Ij described below contain potentially reactive functional groups, for example amino, hydroxyl, thiol and carboxylic acid groups, that may interfere with the desired reaction, it may be advantageous to employ protected forms of the intermediate. Methods for the selection, introduction and subsequent removal of protecting groups are well known to those skilled in the art. (See, e.g., T. W. Greene & P. G. M. Wuts, "Protective Groups in Organic Synthesis" John Wiley & Sons, Inc., New York 1999). Such protecting group manipulations are assumed in the discussion below and not described explicitly. Generally reagents in the reaction schemes are used in equimolar amounts; however, in certain cases it may be desirable to use an excess of one reagent to drive a reaction to completion. This is especially the case when the excess reagent can be readily removed by evaporation or extraction. Bases employed to neutralize HCl in reaction mixtures are generally used in slight to substantial excess (1.05 — 5 equivalents). In the first process of the invention a compound of Formula I or I* wherein Q =
O is prepared by reaction of an amine of formula II with a chloroformate of formula III in the presence of an organic or inorganic base, for example N.N-diisopropylethylamine or K2CO3, in an inert solvent such as CH2Cl2, MeCN or THF at -200C to 800C, preferably O0C to 250C for between 0.5 h and 24 h.
Figure imgf000059_0001
III I
Q = O
Many spirocyclic amines of Formula II can be prepared by previously described routes or can be purchased. Tert-butyl spiro[indoline-3,4'-piperidine]-l-carboxylate (Formula II wherein K, L, Y = C; X = N; R1, K3 L and R2 form a fused benzene ring; n = 0; s = 1 ; t = 2; R4 = CO2t-Bu; R5 = H; R3 absent; single bonds from L to X and X to Y):
Figure imgf000059_0002
can be prepared from benzyl spiro[indoline-3,4'-piperidine]-l'-carboxylate as disclosed in Example 21 of US Patent No. 7,045,527, which is hereby incorporated by reference.
The following substituted tert-butyl spiro[indoline-354'-piperidine]-l-carboxylate were purchased from WuXi Pharmatech (Shanghai, China):
Figure imgf000059_0003
(±)-2-(2,3-Dihydrospiro[indene-l,4'-piperidine]-3-yl)acetic acid (Formula II wherein K, L, X, Y = C; R1, K, L and R2 form a fused benzene ring; n = 0; s = 1 ; t = 2; R4 = CH2CO2H; R5 = H; R3 absent; single bonds from L to X and X to Y):
Figure imgf000060_0001
can be prepared by deprotection of 2-(l'-(tert-butoxycarbonyl)-2,3-dihydrospiro[indene- l,4'-piperidine]-3-yl)acetic acid as disclosed in Example 98 (Steps A and B) of US Patent No. 5,578,593, which is hereby incorporated by reference.
The parent compound and the following substituted (±)-2-(2,3- dihydrospiro[indene-l,4'-piperidine]-3-yl)acetic acid were purchased from WuXi Phaππatech (Shanghai, China) as their N-Boc or ethyl ester derivatives:
Figure imgf000060_0002
Figure imgf000060_0003
Ethyl 2-(7-bromospiro[indene-l54'-piperidine]-3(2H)-ylidene)acetate was purchased from WuXi Pharmatech (Shanghai, China):
Figure imgf000061_0001
2-(3-azaspiro[5.5]undecan-9-yl)acetic acid was purchased from WuXi
Pharmatech (Shanghai, China):
Figure imgf000061_0002
Tert-butyl S.Q-diazaspirofS.SJundecane-S-carboxylate (Formula II wherein K, L, X, Y = C; M = N; R1, R2, R4 and R5 = H; n = 1; s = 1; t = 2; R3 = t-BuOCO; single bonds from K to L, L to M5 M to X and X to Y):
Figure imgf000061_0003
can be prepared from l-benzylpiperidin-4-one as disclosed in Example 1 of US Patent No. 5,451.578, which is hereby incorporated by reference. This compound was purchased from WuXi Pharmatech (Shanghai, China).
Tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (Formula II wherein K, X, Y = C; L = N; n = 0; s = 1 ; t = 2; R1, R4 and R5 = H; R2 = t-BuOCO; single bonds from K to L, L to X and X to Y):
Figure imgf000061_0004
can be prepared from 8-benzy]-2-oxa-8-azaspiro[4.5]decane-l,3-dione as disclosed in Example 19 (Steps A- G) of US Published Patent Application 2003/055244, which is hereby incorporated by reference. This compound was purchased from WuXi Pharmatech (Shanghai, China).
Tert-Butyl 2,7-diazaspiro[4.5]decane-2-carboxylate (Formula II wherein K5 X5 Y = C; L = N; n = 0; s = 2; t = 1; R1, R4 and R5 = H; R3 = t-BuOCO; single bonds from K to L, L to X and X to Y):
Figure imgf000062_0001
was purchased from WuXi Pharmatech (Shanghai, China) (catalog number SA-008). 2.3-Dihydrospiro[indene-l,4'-piperidine] (Formula II wherein K, L, X- Y = C;
R1, K, L and R2 form a fused benzene ring; n = 0; s = 1 ; t = 2; R4 and R5 = H; R3 absent; single bonds from L to X and from X to Y):
Figure imgf000062_0002
can be prepared from indene using the procedures disclosed by Chambers, M. S., et al., J. Med Chem. 1992, 35, 2033-2039, Scheme IL This compound was purchased from WuXi Pharmatech (Shanghai, China).
Spiro[fluorene-9,4r-piperidine] (Formula II wherein K, L, X5 Y = C; R1, K, L and R2 form a fused benzene ring; R4, X5 Y and R5 form a fused benzene ring; n = 0; s = 1 ; t = 2; R3 is absent; single bonds from L to X):
Figure imgf000062_0003
can be prepared from fluorene as disclosed in Example 17 (Steps A — B) of US Patent No. 5,578,593, which is hereby incorporated by reference. Ethyl spiro[indene-l,4'-piperidine]-3-carboxylate (Formula II wherein K, L3 X, Y = C; R1, K5 L and R2 form a fused benzene ring; n = 0; s = 1 ; t = 2; R4 = CH2CO2Et; R5 = H; R3 absent; single bond from L to X and double bond from X to Y):
Figure imgf000063_0001
can be prepared by deprotection of l'-tert-butyl 3-ethyl spiro[indene-l,4'-piperidine]-r,3- dicarboxylate which can be prepared from tert-butyl 3-oxo-2,3-dihydrospiro[indene-l34'- piperidine]-l'-carboxylate as disclosed in Example 1 (Steps A - C) of US Patent No. 5,965,565, which is hereby incorporated by reference. This compound was purchased from WuXi Pharmatech (Shanghai, China). (±)-253-Dihydrospiro[indene-l,4'-piperidine]-3-carboxylic acid (Formula II wherein K, L. X, Y = C; R1 , K, L and R2 form a fused benzene ring; n = 0; s = 1 ; t = 2; R4 = CO2H; R5 = H; R3 absent; single bonds from L to X and from X to Y):
Figure imgf000063_0002
can be prepared by deprotection of r-(tert-butoxycarbonyl)-2,3-dihydrospiro [indene- 1 ,4'-piperidine]-3-carboxylic acid which can be prepared from tert-butyl 3-oxo-2.3- dihydrospiro[indene-l,4'-piperidine]-r-carboxylate as disclosed in Example 1 (Steps A — D) of US Patent No. 5,965,565, which is hereby incorporated by reference. This compound was purchased from WuXi Pharmatech (Shanghai. China). l,3-Dihydrospiro[indene-2,3'-piperidine] (Formula II wherein K, L, X5 Y = C; R2, L, X and R4 form a fused benzene ring; n = 0; s = 2; t = 1 ; R1 and R5 = H; R3 is absent; single bonds from K to L and from X to Y):
Figure imgf000063_0003
can be prepared from ethyl nipecotate using the procedures disclosed by Yang, L., et al., Bioorg. Med. Chem. Lett. 1998, 8, 107-112, Scheme 3.
(±)-2.3-Dihydrospiro[indene-l .3 '-pyrrolidine] (Formula II wherein K, L, X, Y = C; R1, K, L and R4 form a fused benzene ring; n = 0; s = 1; t = 1; R4 and R5 = H; R3 is absent; single bonds from L to X and from X to Y):
Figure imgf000064_0001
can be prepared as described in Sarges R., et al.3 J. Med. Chem. 1988, 31, 230-243 (Compound 95, Table XVI). l,4-dioxa-8-azaspiro[4.6]undecane (Formula II wherein K and Y = O; L and Y = C; n = 0; s = 2; t = 2; R2 and R4 = H; M5 R1, R3 and R5 are absent; single bonds from K to L, from L to X and from X to Y):
Figure imgf000064_0002
can be prepared from ethyl hexahydro-4-oxoazepine-l-carboxylate as disclosed in Example A3 (Steps (a) and (b)) of US Published Patent Application 2003/0139393, which is hereby incorporated by reference.
3H-spiro[isobenzofuran-l34'-piperidine] (Formula II wherein R1, K, L and R ,22 form a fused benzene ring; X is C; Y is O; n = 0; s = 1; t = 2; R4 is H; M, R3 and R5 are absent; single bonds from L to X and from X to Y):
Figure imgf000064_0003
can be prepared as described in Cheng, C. Y., et al., Tetrahedron 1996, 52, 10935. 3H- spiro[isobenzofuran-l,4'-piperidine] was purchased from J & W PharmLab LLC (Morrisville. PA, USA). 2H-spiro[benzofuran-354'-piperidine] (Formula II wherein R , K3 L and R" form a fused benzene ring; X is O; Y is C; n - 0; s = 1 ; t = 2; R5 is H; M5 R3 and R4 are absent; single bonds from L to X and from X to Y):
Figure imgf000065_0001
can be prepared as described in Parham, W. E., et al., J. Org. Chem. 1976, 41, 2628.
5-chloro-l-(methyIsulfonyl)spiro[indoline-3,3'-pyrrolidine] (Formula II wherein R1, K. L and R2 form a fused chlorine substituted benzene ring; X is N; Y is C; n = 0; s = 1 ; t = 1 ; R4 is SO2Me; R5 is H; M and R3 and absent; single bonds from L to X and from X to Y):
Figure imgf000065_0002
can be prepared as disclosed in Example 3 (Steps A - C) of WO 2005/061512 Al5 which is hereby incorporated by reference.
3,4-Dihydro-2H-spiro[naphthalene-l,3'-pyrrolidine] (Formula II wherein R1, K. L and R2 form a fused benzene ring; K5 L, M, X and Y are C; n = 1 ; s = 1 ; t = 1 ; R3, R4 and R3 are H; single bonds from L to M5 from M to X and from X to Y):
Figure imgf000065_0003
can be prepared as described in Crooks, P. A., et al., J. Med. Chem. 1980, 23, 679.
3,4-dihydro-2H-spiro[naphthalene-l,4'-piperidine] was purchased from WuXi Pharmatech (Shanhai, China):
Figure imgf000065_0004
Tert-butyl 1 H-spiro[isoquinoline-454'-piperidine]-2(3H)-carboxylate was purchased from WuXi Pharmatech (Shanhai, China):
Figure imgf000066_0001
6-Methoxy-3,4-dihydro-2H-spiro[isoquinoline-l ,4'-piperidine] :
Figure imgf000066_0002
was prepared as disclosed in Procedure A in US 7,109,207 (Column 25, Line 5), which is hereby incorporated by reference.
Spiro[chroman-2,4'-piperidine] (Formula II wherein R2, L, M and R3 form a fused benzene ring; K = O; M, L, X and Y are C; n = 1 ; s = 1; t = 2; R4 and R5 are H; single bonds from L to M, from M to X and from X to Y):
Figure imgf000066_0003
can be prepared as disclosed in Example 12 (Step A) of US Patent No. 5,536,716, which is hereby incorporated by reference.
Spiro[chroman-2,4'-piperidine]-4-carboxylic acid (Formula II wherein R2, L5 M and R3 form a fused benzene ring; K = O; L, M, X and Y are C; n = 1 ; s = 1 ; t = 2; R4 is CO2H; R5 is H; single bonds from L to M5 from M to X and from X to Y):
Figure imgf000066_0004
was prepared by deprotection of 1 '-(tert-butoxycarbonyl)spiro[chroman-2,4'-piperidine]- 4-carboxylic acid, which was purchased from WuXi Pharmatech (Shanghai, China) (catalog number BBA-0011).
2-(spiro[chroman-2,4'-piperidine]-4-yl)acetic acid (Formula II wherein R2, L5 M and R3 form a fused benzene ring; K = O; L, M, X and Y are C; n = 1; s = 1 ; t = 2; R4 is CH2CO2H; R5 is H; single bonds from L to M, from M to X and from X to Y):
Figure imgf000067_0001
was prepared by deprotection of 2-(l'-(tert-butoxycarbonyl)spiro[chroman-2.4'- piperidine]-4-yl)acetic acid, which was purchased from WuXi Pharmatech (Shanghai, China) (catalog number BBA-OO 12) .
In the first process of the invention, chloroformates of formula III are prepared by reaction of alcohols of formula IV with phosgene or triphosgene in an inert solvent such as toluene, CH2CI2 or THF in the presence of a base such as pyridine at -200C to 8O0C5 preferably 00C to 25°C for between 0.5 h and 24 h.
COCI2
O
R7OH + or . JJ
R7O-^CI CI3COC(=O)OCCI3
In the second process of the invention, a compound of Formula I or I* wherein Q = NH is prepared by reaction of an amine of formula II with an isocyanate of formula V in the presence of an organic or inorganic base, for example N3N-diisopropylethylamine or K2CO3, in an inert solvent such as CH2Cl2. MeCN or THF at -200C to 8O0C5 preferably 00C to 25°C for between 0.5 h and 24 h.
Figure imgf000068_0001
Il V 1
Q = NH
Isocyanates of formula V are prepared by reaction of amines of formula VI with phosgene or triphosgene in, for example, a mixture of CH2Cl2 and satd aq NaHCC>3 at -100C to80°C, preferably 00C to 25°C for between 0.5 h and 24 h.
COCI2
R7NH2 + or ^ R?NCO
CI3COC(=O)OCCI3
Vl V
In the third process of the invention, a compound of Formula I or I* wherein Q = NR is prepared by reaction of an amine of formula II with a compound of Formula VII wherein LG is a leaving group such as halide, aryloxide or azole, for example chloride, p- nitrophenoxide or imidazolide, in an inert solvent such as CIkCl23 MeCN or THF at O0C to 1200C, preferably 25°C to 75°C for between 0.5 h and 24 h.
Figure imgf000068_0002
Intermediates of formula VII wherein LG = aryloxide are prepared by reaction of amines of formula VIII with an aryl chloroformate IX in, for example, MeCN or CH2Cl2 in the presence of DIEA or powdered NaHCO3 at -100C to 500C5 preferably 00C to 25°C for between 0.5 h and 24 h. O " O
R'NHRβ + C)AOAr _ R -NΛLG ,
R6 vπl 'X VII (LG = OAr)
Intermediates of formula VII wherein LG = Cl and R6 is not H are prepared by treatment of amines of formula VIII with phosgene or triphosgene at -70°C to 25°C in an inert solvent such as CH2Cl2, THF or MeCN for between 30 min and 24 h.
Figure imgf000069_0001
VIII (R6 ≠ H) VII (LG = CI, R6 ≠ H)
Intermediates of formula VII wherein LG = 1-imidazolyl and are prepared by treatment of amines of formula VIII with carbonyl diimidazole in an inert solvent such as CH2Cl25 THF, toluene or MeCN at -400C to 600C, preferably at -100C to 300C, for 15 min to 12 h.
Figure imgf000069_0002
Vl11 VIl (LG = 1-imιdazolyl)
In the fourth process of the invention, a compound of Formula I or I* wherein Q = NR6 is prepared by reaction of an intermediate of formula IX, wherein LG is a leaving group such as such as halide, aryloxide or azole, for example chloride, p-nitrophenoxide or imidazolide, with an amine of formula VIII in an inert solvent such as CH2Cl2, MeCN or THF at 00C to 1200C, preferably 25°C to 75°C for between 0.5 h and 24 h.
Figure imgf000069_0003
Intermediates of Formula IX are prepared from intermediates of Formula II using procedures and conditions analogous to those described above for the preparation of intermediates of Formula VII from amines of Formula VIII.
In the fifth process of the invention, a compound of Formula I or I* wherein Q = O is prepared by reaction of an intermediate of formula IX5 wherein LG is a leaving group such as such as halide, aryloxide or azole, for example chloride, p-nitrophenoxide or imidazolide, with an alcohol of formula IV an inert solvent such as CH2Cl2, MeCN or THF at 25°C to 1500C, preferably 25°C to 1000C for between 0.5 h and 24 h.
Figure imgf000070_0001
In the sixth process of the invention, a compound of Formula I or I* is prepared by derivatizing compound of Formula I or I* that has a reactive site such as an amine or carboxylic acid. Examples of the sixth process include the following: a) reaction of a compound of Formula I or I* wherein X = N and R4 = H with an acid chloride of Formula X in an inert solvent such as CH2Cl2, toluene or THF in the presence of a soluble organic base such as pyridine or triethylamine or in the presence of an aqueous base (Schotten-Baumann conditions) at -40°C to 500C3 preferably from -200C to 5°C for between 0.5 h and 30 h, to give a compound of Formula I or Pwherein X = N and R4 = COR6:
Figure imgf000070_0002
b) reaction of a compound of Formula I or I* wherein X = N and R4 = H with a sulfonyl chloride of Formula XI in an inert solvent such as CH2Cl2 or THF in the presence of an amine base such as pyridine or DMAP at 00C to 1250C5 preferably 200C to 1000C5 to give a compound of formula I or I* wherein X = N and R4 = SO2R6:
Figure imgf000071_0001
I Xl I
X = N, R4 = H X = N, R4 = SO2R6 c) reaction of a compound of Formula I or I* wherein X = N and R4 = H with a chloroformate of Formula XII in the presence of an organic or inorganic base, for example N5N-diisopropylethylarnine or K2CO3, in an inert solvent such as CH2Cl25 MeCN or THF at -2O0C to 800C5 preferably 00C to 25°C for between 0.5 h and 24 h to give a compound of formula I or I* wherein X = N and R4 = CO2R6:
Figure imgf000071_0002
I XII ,
X = N, R4 = H χ _ N) R4 _ CO2R6
d) reaction of a compound of Formula I or I* wherein X = C and R4 = ACO2H with an alcohol of Formula XIII in the presence of an acid such as anhydrous HCl gas at 00C to 25°C for between 0.5 h and 24 h, to give a compound of formula lor I* wherein X = C and R4 = ACO2R6:
Figure imgf000072_0001
R4 = ACOoH R6 = alkyl, alkylaryl R4 = ACO2R6 R6 = alkyl, alkylaryl e) reaction of a compound of Formula I or I* wherein X = CH and R4 = ACO2H with an amine of Formula XIV in the presence of a peptide bond forming reagent such as EDC/HOBt, PyBOP or HATU in CH2Cl2 or DMF at O0C to 400C for between 0.5 h and 24 h to give a compound of formula I or I* wherein X = CH and R4 = ACON(R6)2:
Figure imgf000072_0002
f) reaction of a compound of formula I or I* wherein X = C and R4 = ACONH2 with a dehydrating agent such as trifluoroacetic anhydride or POCl3 in the presence of pyridine or 2,6-1 utidine in CH2Cl2 or THF at -70°C to 250C for 0.5 h give a compound of formula I or I* wherein X = C and R4 = AC≡N:
Figure imgf000073_0001
I
R4 = ACONHp R4 = ACN g) reaction of a compound of Formula I or I* wherein X = C and R4 = AC≡N with azidotrimethylsilane in toluene or xylenes in the presence Of(Bu3Sn)2O at 8O0C to 175°C for between 0.5 h and 24 h to give a compound of formula I or I* wherein X = C and R4 = A-(5-tetrazolyl):
Figure imgf000073_0002
R4 = ACN R4 = A-5-tetrazole h) reaction of a compound of Formula I or I* wherein X = C and R4 = ACO2H with a sulfonamide of formula XV in the presence of carbonyl diimidazole in an inert solvent such as CH2Cl2 or THF at 00C to 50°C to give a compound of Formula I or I* wherein X = C and R4 = AC(O)NR6SO2R6:
Figure imgf000074_0001
R4= ACO1H R4 = ACON(R6)SO,R6 i) reaction of a compound of Formula I or I* wherein R7 is a bi- or tricycloalkyl group bearing a CO2Me substituent with an alkali metal hydroxide in a mixture of water and a lower alkanol or THF at 00C to 50°C between 3 h and 24 h to give a compound of Formula I or I* wherein R7 is a bi- or tricycloalkyl group bearing a CO2H substituent:
Figure imgf000074_0002
R7 = a bi- or tricycloalkyl group R7 = a bi- or tricycloalkyl group substituted with CO2Me substituted with CO2H j) reaction of a compound of Formula I or I* wherein R7 is a bi- or tricycloalkyl group bearing a CO2Me substituent with a nucleophilic species such as iodide or a thiol anion to give a compound of Formula I or I* wherein R7 is a bi- or tricycloalkyl group bearing a CO2H substituent:
Figure imgf000075_0001
1 I
R7 = a bi- or tricycloalkyl group R7 = a bι- or tricycloalkyl group substituted with CO2Me substituted with CO2H k) a two step reaction of a compound of Formula I or I* wherein R7 is a bi- or tricycloalkyl group bearing a CO2H- substituent with thionyl chloride or oxalyl chloride in CH2Cl2 at -200C to 800C for between 0.5 h and 24 h to convert the CO2H substituent to an acid chloride substituent followed by treatment with at least one equivalent of ammonia in an inert solvent such as CH2Cl2 or THF, optionally in the presence of a base such as triethylamine or pyridine, at -2O0C to 400C to give a compound of Formula I or I* wherein R7 is a bi- or tricycloalkyl group bearing a CONH2 substituent:
Figure imgf000075_0002
I I
R7 = a bi- or tricycloalkyl group R7 = a bi- or tricycloalkyl group substituted with CO2H substituted with CONH2 1) reaction of a compound of Formula I or I* wherein R7 is a bi- or tricycloalkyl group bearing a CO2Me substituent with an alkali borohydride in THF at -200C to 500C for between 1 h and 24 h to give a compound of Formula I or I* wherein R7 is a bi- or tricycloalkyl group bearing a CH2OH substituent:
Figure imgf000076_0001
I
. R7 = a bi- or tricycloalkyl group R = a bi- or tricycloalkyl group substituted with CO2Me substituted with CH2OH ■
Purification Methods
Unless otherwise specified, prep HPLC refers to preparative reverse phase HPLC on a C- 18 column eluted with a water/acetonitrile gradient containing 0.01 % TFA run on a Gilson 215 system.
Analytical Methods LC-MS Method 1
Column: Chromolith SpeedRod, RP-18e, 50 x 4.6 mm; Mobil phase: A: 0.01%TF A/water, B: 0.01%TF AZCH3CN; Flow rate: 1 mL/min; Gradient:
Figure imgf000076_0002
LC-MS Method 2
Column: YMC ODS-AQ5 S-5mm; 12nm5 50 x 2.0 mm ID; Column temperature 40 °C; Mobil phase: A: H2O+ 0.1% TFA5 B: MeCN+ 0.05% TFA; Flow rate: 0.8 mL/min; Gradient: Time (min) A% B%
0.00 100 0
0.4 100 0
2.00 40 60
2.50 40 60
2.51 100 0
4.00 100 0
LC-MS (16 min) Method 3
Column: Chromolith SpeedRod, RP-18e, 50 x 4.6 mm; Mobil phase: A:
0.01 %TF A/water, B: 0.01%TFA/CH3CN; Flow rate: 1 mL/min; Gradient:
Figure imgf000077_0001
Method 4 (10-80)
Figure imgf000077_0002
Method 5 (30-90)
Figure imgf000078_0001
Method 6 (50-100)
Figure imgf000079_0001
Synthetic Preparations
Preparation 1 2-Adamantyl isocyanate
A vigorously stirred mixture of 2-aminoadamantane hydrochloride (5.01 g, 26.7 mmol), CH2CI2 (50 mL) and satd aq NaHCO3 (50 mL) was cooled in an ice bath. After 15 min, solid triphosgene (2.64 g, 8.9 mmol) was added. The mixture was stirred in the ice bath for 30 min and the layers were separated. The aqueous layer was extracted with CH2Cl2 (100 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4 and concentrated under reduced pressure to afford the title compound (3.55 g, 75%) as a white solid.
Preparation 2 2-Adamantyl chloroformate The title compound was prepared from 2-adamantanol as disclosed in Example 74 (Step (a)) of US Patent No. 5.270,302, which is hereby incorporated by reference.
Preparation 3
1 -Methoxycarbonyl-4-adamantyl chloroformate
Figure imgf000080_0001
Step 1
A stirred solution of 4-oxoadamantane-l-carboxylic acid (4.42 g, 22.8 mmol) in MeOH (100 mL) was cooled in an ice bath and NaBH4 tablets (4 x 1 g, 106 mmol) were added at 15 min intervals. The ice bath was allowed to melt and the mixture was stirred overnight at rt and concentrated under reduced pressure. The residue-was diluted with 5% aq HCl (100 mL) and extracted with ether (2 x 125 mL). The combined ether extracts were dried over MgSO4 and concentrated to give 4-hydroxyadamantane-l- carboxylic acid (4.47 g, quant) as an off-white solid which was used directly. Step 2
To a stirred solution of 4-hydroxyadamantane-l-carboxylic acid (4.47 g, 22.8 mmol) in MeOH (75 mL) was added 4 M HCl in dioxane (25 mL, 100 mmol). The mixture was stirred at rt for 2 d and concentrated. The residue was purified by chromatography on a 40-g silica cartridge eluted with a 0 — 80% EtOAc in hexanes gradient to afford methyl 4-hydroxyadamantane-l-carboxylate (4.04 g, 84%) as a clear, colorless oil. Step 3
A stirred solution of methyl 4-hydroxyadamantane-l-carboxylate (1.01 g, 4.8 mmol) and pyridine (0.38 mL, 4.8 mmol) in CH2Cl2 (25 mL) was cooled in an ice bath and a solution of triphosgene (0.48 g, 1.6 mmol) in CH2CI2 (10 mL) was added dropwise over 15 min. The mixture ice bath was allowed to melt and the mixture was stirred for 3 h. The mixture was evaporated to dryness and the residue was triturated with EtOAc (100 mL). The filtrate was concentrated to afford l-methoxycarbonyl-4-adamantyl chloro formate (1.19 g, 91%) as an oil which solidified on standing.
Preparation 4 Spiro [indene-2 ,3 '-piperidin] - 1 (3H)-one
Figure imgf000081_0001
Step 1
To a solution of ethyl piperidine-3-carboxylate (67.74 g, 266 mmol) in dry CH2Cl2 (300 mL) was added TEA (40.34 g, 399 mmol) at 00C. Benzoyl chloride (41.13 g, 293 mmol) was added slowly to control any rise in reaction temperature. After addition was complete, the mixture was stirred at rt overnight. The mixture was washed with IN aq HCl and brine. The organic layer was dried with anhydrous Na2SO4 and concentrated to leave a residue, which was purified by silica gel column chromatography (petroleum/ethyl acetate 5 : 1 to 3 : 1 ) to afford ethyl 1 -benzoylpiperidine-3-carboxylate (62.63 g, 90%). 1H NMR (CD3OD, 400 MH2): δ=1.41 (t, 3H), 1.52 (m, 2H), 1.85 (m, 2H), 2.36 (s, IH), 3.29 (m, 2H), 3.81 (m, 4H), 7.22 (m, 3H), 7.42 (m, 2H). Step 2
To a solution of ethyl l-benzoylpiperidine-3-carboxylate (9.22 g, 35 mmol) in dry THF (55 mL) at -78°C was added dropwise LDA (39 mmol, 1.1 eq) in 45 mL of dry THF. After addition, the reaction was stirred for 1 h. Then benzyl bromide (6.54 g, 39 mmol, 1.1 eq) was added dropwise under the an atmosphere OfN2. The reaction was stirred for another 3 h. The solution was added dropwise 5% HCl at 00C and concentrated. The aqueous residue was extracted with CH2Cl2. The combined organic extracts were dried over anhydrous Na2SO4 and evaporated to afford ethyl l-benzoyl-3- benzylpiperidine-3-carboxylate (11.16 g, 91%). 1H NMR (CD3OD5 400 MHZ): δ=1.30 (t, 3H)5 1.50-1.55 (ra, H), 2.75 (m, 2H), 3.65 (m; 4H), 4.09 (m, 2H), 7.08 (m5 2H)5 7.22 (m, 3H), 7.48 (m, 5H). Step 3 Ethyl l-benzoyl-S-benzylpiperidine-S-carboxylate (6.308 g, 18 mmol) was hydrolyzed with 1 N aq NaOH (220 mL) in ethanol (110 mL) for 20 h at rt. The ethanol was removed by rotary evaporation and the aqueous layer was extracted once with CH2Cl2- The pH of the aqueous layer was adjusted to pH=3~4 with 1 N aq HCl and extracted with CH2Cl2 (3 x). The organic phase was dried over anhydrous Na2SO4, filtered and evaporated to give l-benzoyl-3-benzylpiperidine-3-carboxylic acid (3.24 g, 55.7 %). 1H NMR (CD3OD, 400 MHZ): δ=1.12'(m5 3H), 1.50-1.72 (ra, 4H)5 2.18 (m, IH)5 2.75 (d, IH)5 3.05 (m, IH)5 3.16 (m, IH), 4.08 (m, 2H)5 7.08 (m, 2H)5 7.22 (m, 3H), 7.48 (m, 5H). Step 4 A mixture of l-benzoylo-benzyl-piperidine-S-carboxylic acid (6.71 g5 20.7 mmol) and thionyl chloride (2.70 g5 22.77 mmol) in dry CH2Cl2 (25 mL) was heated to reflux for 30 min. The resulting solution was concentrated in vacuum to give a light brown oil. A solution of this oil in dry CH2C12 (25 mL) was added dropwise to a mixture OfAlCl3 (3.59 g, 26.91 mmol) in CH2Cl2 (10 mL) at 00C. The mixture was stirred for 15 min at 00C and then heated to reflux for 45 min. The mixture was cooled and poured onto crushed ice and 12 N aq HCl. The organic layer was separated, washed with 3 N aq HCl, saturated Na2COs5 water and brine. Finally the organic layer was concentrated to give a residue, which was purified by silica gel column chromatography (petroleum/ethyl acetate 5:1 to 1 :1) to afford r-benzoylspiro[indene-2,3'-piperidin]-l(3H)-one (3.24 g, 51 %). 1H NMR (CD3OD, 400 MH2): 6=1.61 (m, 4H), 2.68 (m, 2H)5 3.46 (m, 4H), 7.34 (m, 8H)5 7.64 (m, 2H). Step 5 r-benzoylspiro[indene-2,3'-piperidin]-l(3H)-one (2.476 g, 8.11 mmol) was dissolved in methanol (40 mL). 1 N aq HCl (80 mL) was added dropwise and the mixture was refluxed overnight. The methanol was removed in vaccuo. The pH of the solution was adjusted to 8 using saturated Na2CO3, and the solution was extracted with CH2Cl2. The combined organic extracts were dried over anhydrous Na2SO4 and then concentrated to afford a residue, which was purified by silica gel column chromatography to afford spiro[indene-253'-piperidin]-l(3H)-one (460 rng, 28%). 1H NMR (CD3OD, 400 MHZ): δ=1.63 (m, 2 H), 1.82 (m, 1 H)5 1.87-2.00 (m, 1 H), 2.70 (d, 1 H)3 2.82 (m, 1 H)3 3.00 (m, 3 H)3 3.20 (d, I H), 7.32 (m, 1 H)5 7.45 (m, 1 H)5 7.57 (m5 1 H)5 7.79 (m, 1 H).
Preparation 5 Ethyl 2-(7-bromo-2,3-dihydrospiro[indene-l,4'-piperidine]-3-yl)propanoate
UHMDf JSL
Figure imgf000083_0001
Figure imgf000083_0002
Figure imgf000083_0003
Step 1
To a solution of tert-butyl 7-bromo-3-(2-ethoxy-2-oxoethyl)-2.3- dihydrospiro[indene-l34'-piperidine]-r-carboxylate (500 mg5 1.11 mmol) was added LiHMDS (2.4 mL. 1 M5 2.4 mmol) at -100C under nitrogen. The mixture was stirred for 1 h and CH3I (472 mg, 3.3 mmol) was added. After addition, the mixture was stirred overnight. The solution was quenched with satd aq NH4Cl5 the organic phase was separated, dried and concentrated to give crude product which was purified by preparative TLC to give tert-butyl 7-bromo-3-(l-ethoxy-l-oxopropan-2-yl)-2,3- dihydrospiro[indene-l,4'-piperidine]-l'-carboxylate (60 mg, 11%). 1HNMR: (400MHz, CDCI3): δ= 0.96 (d, 3H), 1.23 (t, 3H)3 1.28 (m, IH)5 1.41 (s, 9H), 1.62 (m, IH), 2.32 (m3 2H)5 2.73 (m, 3H), 3.08 (m, IH)5 3.61 (m, IH)5 4.07 (d, 2H), 4.12 (q, 2H)5 6.94 (m, 2H)5 7.28 (m, IH). Step 2
Tert-butyl 7-bromo-3-(l -ethoxy-1 -oxopropan-2-yl)-2,3-dihydrospiro[indene-l A'- piperidine]-l'-carboxylate (300 mg, 0.645 mol) was dissolved in 20% TFA at 00C. The reaction mixture was stirred for 1 h at rt. The solvent was removed under reduced pressure to give ethyl 2-(7-bromo-253-dihydrospiro[indene-l54'-piperidine]-3- yl)propanoate (235 mg, 100%). 1H NMR: (400MHz, CDCl3): δ= 0.98 (d, 3H)5 1.23 (t, 3H)5 1.61-1.73 (m, 4H)5 2.42 (m5 IH), 2.73 (m, IH), 3.01 (m, IH)3 3.23 (m, 3H)5 3.48 (m5 3H)5 3.68 (d, IH), 4.21 (q, 2H)5 7.03 (m, 2H), 7.38 (d, IH).
Preparation 6 Ethyl 2-(7-bromo-2,3-dihydrospiro[indene-l54'-piperidine]-3-yl)-2-methylpropanoate
EtoOo
Figure imgf000084_0001
Step 1 To a solution of tert-butyl 7-bromo-3-(2-ethoxy-2-oxoethyl)-2,3- dihydrospiro[indene-l,4'-piρeridiπe]-r-carboxylate (500 mg, 1.11 mmol) was added LiHMDS (2.4 mL, 1 M5 2.4 mmol) followed by HMPA at -1O0C under N2. The mixture was stirred for 1 h and CH3I (142 mg, 8.8 mmol) was added to the solution. After addition, the mixture was stirred overnight. The solution was quenched by saturated NH4CI, the organic phase was separated, dried and concentrated to give the crude product which was purified by preparative TLC to give (±)-tert-butyl 7-bromo-3-(l- ethoxy-2-methyl-l-oxopropan-2-yl)-2,3-dihydrospiro[indene-l,4'-piperidine]-r- carboxylate (350 mg, 67%). 1B NMR: (400 MHz5 CDCl3): δ= 1.12 (s, 3H), 1.26 (s, 3H)5 1.30 (m, 3H), 1.32 (m, 2H), 1.48 (s, 9H), 2.29 (m, IH)3 2.42 (m, IH), 2.93 (m, 3H)3 3.16 (m, IH), 3.78 (m, IH)3 4.16 (m, 2H), 4.25 (m, 2H), 6.94 (d, IH) 7.02 (t, IH) 7.37 (d, IH). Step 2
(±)-Tert-butyl 7-bromo-3-(l -ethoxy-2 -methyl -1 -oxopropan-2-yl)-2.3- dihydrospiro [indene-l,4'-piperidine]-r-carboxylate (152 mg, 0.317 mol) was dissolved in 20% TFA at 00C. The mixture was stirred for 1 h at rt. The solvent was removed under reduced pressure to give (±)-ethyΙ 2-(7-bromo-2.3-dihydrospiro[indene-l,4'- piperidine]-3-yl)-2-methylpropanoate which was used without purification (120 mg, 100%).
Preparation 7
4-aminoadamantan- 1 -ol
Figure imgf000084_0002
To 2-aminoadaπiantane (10 g, 54 mmol) was added H2SO4 (150 mL) and HNO3 (15 ml) at O0C and the mixture was stirred overnight. The mixture was poured onto ice and adjusted to pH=10-l 1 using 40% aq NaOH under ice bath. The mixture was extracted with CH2Cl2. The organic layer was dried, filtered and concentrated to give 4- aminoadamantan-1-ol (3.0 g, 14%).
Preparation 8
1 -fluoro-4-aminoadamantane
Figure imgf000085_0001
To the solution of 4-aminoadamantan-l-ol (800 mg, 4.79 mmol) in anhydrous toluene (6 mL) was added DAST (780 mg, 5 mmol) at 00C. The reaction mixture was reflux ed for 8 h. The mixture was cooled to rt and quenched with aq NaHCOs. The mixture was concentrated and extracted with CH2CI2 (2 x). The combined organic extracts were dried, filtered and concentrated to give l-fluoro-4-aminoadarnantane (700 mg), which was used without purification.
Preparation 9 1 ,7-dihydroxy-4-aminoadamantane
Ac2O Br2ZAIBr3
Figure imgf000085_0004
Figure imgf000085_0003
Figure imgf000085_0002
Figure imgf000085_0005
Step 1
A solution of 2-aminoadamantane (20 g, 108 mmol) in dry pyridine (120 mL) was treated with acetic anhydride (12 mL, 128 mmol) and stirred overnight at rt. The mixture was dilute with EtOAc and washed with water, 1 N aq phosphoric acid and brine. The organic layer was dried, filtered and concentrated to give N-(2- adamantyl)acetamide (12.5 g, 60%). 1H NMR (400MHz5 CDCl3): δ=1.57 (m, 2H)5 1.67 (m, 3H), 1.72 (m5 IH)3 1.77 (m, 6H)5 1.85 (m, 2H), 1.94 (s, 3H), 3.97 (t, IH)5 5.78 (br, IH). Step 2 To bromine (20 mL, 40 mmol) and aluminum bromide (3.2 g, 20 mmol) was added N-(2-adamantyl)acetamide (4 g, 20 mmol) in portions. The reaction mixture was heated to 900C and stirred overnight. The mixture was cooled to rt and poured into ice/water. Satd aq sodium bisulfite was added slowly followed by dilution with CH2CI2. The organic layer was separated, washed with brine, dried, filtered and concentrated. The crude product was purified by column chromatography to afford N-(5,7-dibromo-2- adamantyl)acetamide (1.98 g, 28%). Step 3
To N-(5,7-dibromo-2-adamantyl)acetamide (2 g, 5.73 mmol) and Ag2SO4 (3.90 g, 12.6 mmol ) was slowly added concentrated H2SO4 (14 mL). After addition was complete, the reaction mixture was heated to 8O0C for 3 h. The mixture was cooled to rt and poured into ice/water. The mixture was filtered, and the filtrate was neutralized with solid KOH. The mixture was filtered, and the solids were washed with methanol. The filtrate was concentrated, and the residue was triturated with methanol. The mixture was filtered, and filtrate was concentrated. The crude product was purified by preparative TLC (DCM/MeOH=5: 1 ) to give iV-(557-dihydroxy-2-adamantyl)acetamide (192 mg, 15%). 1H-NMR (400MHz5 DMSO): 6=1.21 (m, 2H), 1.42 (m, 6H), 1.74 (m, 2H), 1.77 (m, 3H)5 1.96 (m, 2H), 4.48 (d, IH), 7.65 (m, IH). Step 4
To iV-(5,7-dihydroxy-2-adamantyl)acetamide (110 mg, 0.489 mmol) was added 4N aq HCl (3 mL) slowly. The reaction mixture was heated to 8O0C overnight. The mixture was cooled to rt and concentrated. The residue was treated with satd aq NaHCO3- The water was removed under reduced pressure, and the solid was triturated with methanol. The mixture was filtered, and the solids were washed with methanol. The filtrate was concentrated give to 6-aminoadamantane-l,3-diol (50 mg, 56%). 1H- NMR (400MHz, D2O): δ=l .45 (m, 2H), 1.63 (m, 6H)5 1.73 (m, 4H), 2.12 (m, 2H)5 3.27 (m, IH). Preparation 10 7-chloro-2-(4-methoxybenzyl)spiro[isoindoline-l,4'-piperidine]-3-thione
Figure imgf000087_0001
PMB = 4-methoxybenzyl
Step 1
A 100-mL flask was charged with 3-chloro-2-iodobenzoic (2.43 g, 8.64 mmol, 0.90 equiv) and thionyl chloride (15 mL). The solution was vigorously stirred, then 1 drop of DMF added and the mixture heated to reflux for 4h. During this time the acid dissolved to give a pale yellow solution. The cooled mixture was evaporated and toluene (50 mL) added, then removed in vacuo. The evaporation/dissolution with toluene/evaporation procedure was repeated twice and the pale yellow 3-chloro-2- iodobenzoyl chloride was placed on the vacuum line.
In a separate flask a toluene (30 mL) solution tert-butyl 4-oxopiperidine-l- carboxylate (2.45 g, 12.32 mmol, 1.25 equiv), 4-methoxybenzylamine (1.352 g, 9.6 mmol, 1.0 equiv) and MgSO4 (—20 g) were heated to reflux overnight. The mixture was filtered through a bed of Celite, the cake was washed with toluene (-30 mL) and the filtrate was evaporated. The amber residue was dissolved in CH2CI2 (100 mL) and TEA (1.94 g, 2.7 mL, 19.2 mmol, 2.0 equiv) and DMAP (117 mg, 0.96 mmol, 0.1 equiv) were added. The 3-chloro-2-iodobenzoyl chloride prepared above was dissolved in CH2Cl2 (10 mL) and the resultant solution added to the enamine solution over a ~10 min period, then stirred overnight. The reaction was quenched by addition of 1.0 M aq HCl (100 mL) and the mixture was transferred to a separatory funnel. The organic layer was washed with brine, dried over Na2SO4, filtered, and evaporated. The residue was purified by flash chromatography on silica gel (120 g) eluting with 19-71% EtOAc in hexanes. tert-butyl 4-(3-chloro-2-iodo-N-(4-methoxybenzyl)benzamido)-5,6- dihydropyridine-l(2H)-carboxylate (—3.19 g, -5.47 mmol, -63% yield), contaminated with ~5% 3-chloro-2-iodo-JV-(4-methoxylbenzyl)benzamide, was isolated as a pale yellow foam. Step 2
Tert-butyl 4-(3-chloro-2-iodo-N-(4-methoxybenzyl)benzamido)-5,6- dihydropyridine-l(2H)-carboxylate ( — 3.19 g, ~5.47 mmol) was dissolved in DMF (30 mL) in a three neck flask fitted with a condenser and the mixture was purged with N2 gas for ~1 h. Against a counterflow of N2 the flask was quickly opened and Pd(OAc)2 (61 mg, 0.274 mmol, 5 mol%), rac-BINAP (340 mg, 0.548 mmol. 10 mol%), DIEA (1.56g, 2.1 mL, 11.0 mmol, 2.0 equiv) and Et4NCl (980 mg, 5.47 mmol, 1.0 equiv) were added. The mixture was heated to reflux for 17 h. After this time, the iodide had been consumed and the mixture was cooled to it and evaporated. The residue was taken up in EtOAcZH2O and the layers were separated. The organic layer was washed with brine, dried over Na2 S O4, and evaporated. The crude product was purified by flash chromatography on silica gel, eluting with 20-80% EtOAc in hexanes. tert-butyl 7- chloro-2-(4-methoxybenzyl)-3-oxo-2',3'-dihydro-lΗ-spiro[isoindoline-l,4'-pyridine]-r- carboxylate was isolated as a pale yellow foam (1.72 g, 69%). Step 3
Tert-butyl 7-chloro-2-(4-methoxybenzyl)-3-oxo-2',3l-dihydro-lΗ- spiro[isoindoline-l,4'-pyridine]-r-carboxylate (1.69 g. 3.71 mmol, 1.0 equiv) and PtO2 (100 mg, 0.440 mmol, 12 mol%) were added to a solution of 1 : 1 4.0 M HChMeCN (200 mL). The mixture was transferred to a Parr hydrogenation vessel and hydrogenated at 55 psi for 3 d. After this time the vessel was vented and the pale yellow solution filtered through a bed of Celite. The mixture was evaporated and the residue was dissolved in 1 :1 MeCN: 10% aq K2CO3 (200 mL); Boc2O (1.2 Ig, 5.56 mmol, 1.5 equiv) was added and the mixture was stirred for 17 h. After this time the solution was evaporated and the residue was diluted with EtOAc. The organic layer was washed with 1.0 M aq HCl and brine, dried over Na2SO4, and evaporated. The reduced product was purified by flash chromatography on silica gel, eluting with 20-80% EtOAc in hexanes. Tert-butyl 7- chloro-2-(4-methoxybenzyl)-3-oxospiro [isoindoline- 1 ,4'-piperidine]- 1 '-carboxylate was isolated as a pale yellow foam (0.702g, 1.54 mmol, 42 %). Step 4
Tert-butyl 7-chloro-2-(4-methoxybenzyl)-3-oxospiro[isoindoline- 1 ,4'-piperidine]- l'-carboxylate (50 mg, 0.110 mmol, 1.0 equiv) and Lawesson's reagent (220 mg, 0.55 mmol. 5.0 equiv) were added to toluene (10 mL) and the mixture heated to 800C for 17 h. The mixture was cooled to rt and filtered through a plug of Celite. The filtrate was evaporated and the residue purified by flash chromatography on silica (4 g, eluting with 19-71% EtOAc in hexanes. tert-butyl 7-chloro-2-(4-methoxybenzyl)-3- thioxospiro[isoindoline-l,4'-piperidine]-r-carboxylate (52 mg, 0.11 mmol, >99% yield) was isolated as a pale yellow solid. Step 5
Tert-butyl 7-chloro-2-(4-methoxybenzyl)-3-thioxospiro[isoindoline- 1 ,4'- piperidine]-l'-carboxylate (52 mg, 0.11 mmol) was dissolved in neat TFA (~2 mL). After 0.5 h LC-MS showed removal of the boc group. The mixture was evaporated to afford crude 7-chloro-2-(4-methoxybenzyl)spiro[isoindoline-l54I-ρiperidine]-3-thione as its TFA salt which was used without purification.
7-chloro-2-methylspiro[isoindoline-l;4'-piperidine]-3-thione was prepared following procedures analogous to those described in Preparation 10 using methylamine in Step 1 in place of 4-methoxybenzylamine.
2-methylspiro[isoindoline-1.4'-piperidine]-3-thione was prepared following procedures analogous to those described in Preparation 10 using 2-iodobenzoyl chloride in place of 3-chloro-2-iodobenzoyl chloride and methylamine in place of 4- methoxybenzylamine in Step 1.
Preparation 11 Spiro[isoindoline-l,4'-piperidine]-3-thione
Figure imgf000089_0001
PMB = 4-methoxybenzyl
Step 1 Tert-butyl 2-(4-methoxybenzyl)-3-oxospiro[isoindoline-l ,4'-piperidine]-l '- carboxylate (50 mg, 0.12 mmol, 1.0 equiv) and TFA (7 mL) were heated to 75°C for 19 h. After this time LC-MS showed removal of the Boc- and p-methoxybenzyl groups. The mixture was concentrated to leave crude spiro[isoindoline-l,4'-piperidin]-3-one which was used directly. Step 2
Crude spirofisoindoIine-l^'-piperidinj-S-one was dissolved in 1:1 MeCN: 10% aq K2CO3 (20 mL) and BoC2O (50 mg, 0.23 mmol, 2.0 equiv) added. The mixture stirred for 3 h. The solution was evaporated and the mixture was diluted with EtOAc. The organic layer was washed with 1.0 M aq HCl and brine, dried over Na2SO4, and evaporated. The residue was purified by flash chromatography on silica, eluting with 20-80% EtOAc in hexanes to afford tert-butyl 3-oxospiro[isoindoline-l,4'-piperidine]-l '-carboxylate. - Steps 3 and 4
Tert-butyl 3-oxospiro[isoindoline-l,4'-piperidine]-l '-carboxylate and Lawesson's reagent (-150 mg, -0.37 mmol, - 3equiv) were dissolved in toluene and heated to reflux overnight. The mixture was evaporated, taken up in CH2Cl2,(~l 0 mL) and filtered through a plug of Celite. The fϊtrate was treated with TFA (—2 mL). The mixture was stirred for 3 h at rt and evaporated to afford crude spiro[isoindoline-l,4'-piperidine]-3- thione as its TFA salt.
Preparation 12 Tert-butyl 7-chloro-3-hydroxy-3H-spiro[isobenzofuran-l,4'-piperidine]-l '-carboxylate
Figure imgf000090_0001
Step 1 2.5 M n-BuLi in hexanes (9.2 mL, 23 mmol) was added To a stirred solution of
2,2,6,6-tetramethylpiperidine (3.2 g, 23 mmol) in anhydrous THF (30 mL) at -200C under N2. The mixture was stirred for 1 h at -200C and then cooled to -78°C. 3- Chlorobenzoic acid (1.8 g. 1 L5 mmol) in anhydrous THF (20 mL) was slowly added dropwise and the mixture was stirred for 1 h at -78°C. The mixture was treated with tert- butyl 4-oxopiperidine-l -carboxylate (2.29 g, 11.5 mmol) and the resulting solution was warmed to rt and stirred overnight. The mixture was quenched with water and extracted with EtOAc (3 x 30 mL). The organic layers were combined, washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by chromatography to give tert-butyl 7-chloro-3-oxo-3H-spiro[isobenzofuran-l,4'- piperidine]-l'-carboxylate (500 mg, 13%). 1H NMR (CD3OD): δ = 1.45 (s, 9H), 2.60 (m, 2H), 3.20 (b, 2H), 4.20 (b, 2H), 7.48 (m, IH)5 7.55 (m, IH), 7.75 (m, IH). Step 2.
DIBAL (1 M, 2.4 mL, 2.4 mmol) was added to a solution of tert-butyl-7-chloro-3- oxo-3H-spiro[isobenzofuran-l,4'-piperidine]- l'-carboxylate (200 mg, 0.6 mmol) in CH2Cl2 (5 mL) at -78°C. The mixture was stirred at -700C for 30 min. After the starting material was consumed, the reaction was quenched with methanol, followed by satd aq potassium sodium tartarate tetrahydrate, and stirred for 1 h. The mixture was filtered and the filtrate was extracted with CH2Cl2 (3 x 15 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by preparative TLC to provide tert-butyl 7-chloro-3-hydroxy-3H- spiro[isobenzofuran-l34'-ρiperidine] -l'-carboxylate (160 mg, 78%). 1H NMR (CDCl3): δ = 1.44 (s, 9H), 1.51 (m, 2H)5 1.64 (m, H), 2.30-2.64 (m, 2H), 3.18 (m, 2H), 4.00-4.18 (m, 2H), 6.35-6.56 (m, IH), 7.06 (m, IH), 7.27 (m, 2H).
The following examples are intended to illustrate various embodiments of the invention and are not intended in any way to restrict the scope thereof.
EXAMPLES
Example 1
Tert-butyl 1 '-((2-adamantyl)carbamoyl)spiro[indoline-3,4'-piperidine]- 1 -carboxylate
Figure imgf000091_0001
Figure imgf000091_0003
CDI
Figure imgf000091_0002
A stirred solution of 2-adamantanamine hydrochloride (81.1 mg, 0.432 mmol) and DIEA (557 mg, 4.32 mmol) in anhydrous CH2CI2 (5 mL) was cooled to 00C and CDI (84 mg, 0.52 mmol) was added. The mixture was stirred for Ih at 00C and tert- butyl spiro[indoline-3,4'-piperidine]-l-carboxylate (140 mg, 0.43 mmol) in anhydrous CH2Cl2 (5 mL) was added. The reaction mixture was allowed to warm to it and stirred- overnight. The reaction mixture was concentrated and the residue was purified by preparative TLC to provide tert-butyl r-((2-adamantyl)carbamoyl)spiro[indoline-3,4'- piperidine]-l-carboxylate as a white solid (50 mg, 25%). 1H NMR (CD3OD, 400 MHz): δ=1.58~2.01 (m, 28H)5 2.92 (t, 2H), 3.91 (d, 2H), 4.09 (d, 2H), 5.85 (ds IH), 6.95-7.85 (m, 4H) ; MS: 466 (M++!); LC-MS(4 min) tR = 2.70 min, m/z = 466.
Example 2 N-(2-Adamantyl)spiro[indoIine-354'-piperidine]-r-carboxamide
Figure imgf000092_0001
A 10-mL round-bottomed flask was charged with tert-butyl 1 '-((2- adamantyl)carbamoyl)spiro[indoline-3,4'-ρiperidine]-l-carboxylate (50 mg, 0.107 mmol) and 20 % trifluoroacetic acid in CH2Cl2 (2 mL). The mixture was stirred for Ih at 00C. The solution was concentrated under vacuum and the crude product was purified by preparative HPLC to provide N-(2-adarnantyl)spiro[indoline-3,4'-piperidine]-r- carboxamide (lOmg, 25%). 1H NMR (CD3OD, 400 MH2): 5=1.60-2.00 (m, 18H), 3.00 (t, 2H), 3.86 (d, 3H)5 4.08 (d, 2H), 7.40-7.50 (m, 4H); ); LC-MS(4 min) tR = 1.93 min, m/z = 366 (M++!).
Example 3
(±)-2-(r-((2-AdamantyI)carbamoyl)-2,3-dihydrospiro[indene-l,4'-piperidine]-3-yl)acetic acid
Figure imgf000093_0001
Step 1
2-(r-(Tert-butoxycarbonyl)-2,3-dihydrospiro[indene-l34'-piperidine]-3-yl)acetic acid (200 mg, 0.58 mmol) was added to a solution of 20% trifluroacetic acid in anhydrous CH2CI2 (3 mL) at 00C. The reaction solution was stirred at rt for 2 h until the starting material had been consumed. The solution was concentrated to give crude 2- (2,3-dihydrospiro[indene-l,4'-piperidine]-3-yl)acetic acid (160 mg) which was used in the next step without further purification. Step 2
To a solution of 2-aminoadamantane hydrochloride (120 mg, 0.64 mmol) and CDI (141 mg, 0.87mmol) in anhydrous CH2Cl2 (4 mL) at 00C was added DIEA (374 mg, 2.90 mmol). The mixture was stirred at 00C for I h. A solution of compound 2-(2,3- dihydrosρiro[indene-l54'-piperidine]-3-yl)acetic acid (142 mg, 0.58 mmol) was added dropwise slowly. The mixture was stirred at rt overnight and concentrated to give the crude product. A portion of the crude product was purified by preparative HPLC to give 2-(l '-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-l ,4'-piperidine]-3-yl)acetic acid (60 mg, 36 %). 1H NMR: (400MHz, CDCl3): 5=1.56-1.73 (m5 6H)3 1.74-1.90 (m, 10H), 1.95 (m, 2H)5 2.10 (m, IH), 2.45 (m, IH)5 2.60 (m, IH), 3.01(m, 3H), 3.65 (m, IH), 3.87-3.99 (m, 3H), 7.15-7.26 (m, 4H); LC-MS(4 min) tR = 2.70 min, m/z = 423(M++!).
Example 4
(±)-Methyl 2-(l '-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-l ,4'-piperidine]-3- yl)acetate
Figure imgf000093_0002
To a solution of 2-(r-((2-adamantyI)carbamoyl)-2,3-dihydrosρiro[indene-l,4'- piperidine]-3-yl)acetic acid (150 mg, 0.355 mmol) in methanol (2 mL) at 0 0C was added thionyl chloride (54 mg, 0.46 mmol). The mixture was stirred at rt overnight and concentrated. The residue was purified by preparative TLC to give methyl 2-(l'-((2- adamantyl)carbamoyl)-2,3-dϊhydrospiro[indene-l,4'-piperidine]-3-yl)acetate (62.8 mg, 41%). 1H NMR (400MHz, CDCl3): 6=1.52-1.73 (m, 6H), 1.73-1.81 (m, 3H), 1.82-1.90 (m, 7H)5 1.95 (m, 2H), 2.10 (m, IH)5 2.45 (m, IH), 2.60 (m, IH)5 3.01(m5 3H)3 3.65 (m, IH)5 3.74 (S5IH)5 3.86 (d, IH), 3.99 (m, 2H)5 4.87"(S5IH)5 7.13-7.26 (m, 4H); LC-MS(4 min) tR = 2.38 min, m/z = 437(M+-t-l).
Example 5 Separation of the enantiomers of Methyl 2-(r-((2-adamantyl)carbamoyl)-2.,3- dihydrospir"o[indene-l,4'-piperidine]-3-yl)acetate
Methyl 2-(l '-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-l ,4'-piperidine]- 3-yl)acetate was submitted to preparative HPLC on a 10 mm x 250 mm Chiral Technologies Chiralcel OD-H column eluted with 4 mL min"1 of 10% isopropanol in hexanes containing 0.025% diethylamine for 30 min. The isomer that eluted first (tR = 23 min) was designated Example 5 A. 1H NMR (CDCl3) δ = 2.05 (m, IH), 2.43 (m, IH)5 2.60 (m, IH), 2.92 (m. IH)5 3.05 (m5 2H), 3.65 (m, IH), 3.74 (s, 3H), 3.90 (d, IH), 4.00 (m, IH), 4.82 (d, IH).
The isomer that eluted second (tR = 26.5 min) was designated Example 5B. 1H NMR (CDCl3) δ = 2.05 (m, IH)52.43 (m, IH)5 2.60 (m, IH), 2.92 (m5 IH), 3.05 (m, 2H)5 3.65 (m, IH), 3.74 (s, 3H), 3.90 (d, IH)54.00 (m, IH)5 4.82 (d, IH).
Example 6 2-(l '-((2-Adamantyl)carbamoyl)-253-dihydrospiro [indene- 1 ,4'-piperidine]-3-yl)acetic acid
Figure imgf000094_0001
To a stirred solution of methyl 2-(r-((2-adamantyl)carbamoyl)-2.3- dihydrospiro[indene-l,4'-piperidine]-3-yl)acetate isomer A (2.0 mg, 5 μmol) in water (0.25 mL), THF (0.25 mL) and methanol (0.5 mL) was added LiOH-H2O (10 mg, 0.23 mmol). The mixture was stirred overnight at rt. The mixture was diluted with 5% aq HCl (10 mL) and extracted with EtOAc (2 x 40 mL). The combined organic extracts were dried over Na2SO4 and concentrated to leave crude 2-(l'-((2- adamantyl)carbamoyl)-2,3-dihydrospiro[indene-l ,4'-piperidine]-3-yl)acetic acid isomer A (3 mg, quant) as an oil. 1H NMR (CDCl3) δ = 2.49 (m, IH), 2.63 (m, IH), 3.00 (m, IH), 3.1 (IH), 3.65 (IH)5 3.92 (IH), 4.02 (2H); LC-MS(3 min) tR = 1.90 min, m/z = 423.
The same procedure was applied to methyl 2-(l '-((2-adamantyl)carbamoyl)-2,3- dihydrospiro[indene-l,4'-piperidine]-3-yl)acetate isomer B (2.7 mg, 6 μmol) to afford crude 2-(l '-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-l ,4'-piperidine]-3- yl)acetic acid isomer B (2.85 mg, quant) as an oil. 1H NMR (CDCl3) δ = 2.49 (m, IH), 2.63 (m, IH), 3.00 (m, IH), 3.1 (IH), 3.65 (IH), 3.92 (IH), 4.02 (2H); LC-MS(3 min) tR = 1.90 min, m/z = 423.
Example 7 1 -Acetyl-N-(2-adamantyl)spiro[indoline-3,4'-ρiperidine]- 1 '-carboxamide
Figure imgf000095_0001
To a solution N-(2-adamantyl)spiro[indoline-3,4'-piρeridine]-l '-carboxamide (50 mg, 0.108 mmol) and DIEA (27.86 g, 0.22mmol) in dry CH2Cl2 (2 mL) at O0C under nitrogen was added dropwise a solution of acetyl chloride (9.28 mg, 0.12 mmol) in CH2Cl2 (0.5 mL). The mixture was stirred overnight at rt and evaporated to give a residue, which was purified by preparative HPLC to provide a white solid 1 -acetyl-N-(2- adamantyl)spiro[indoline-3,4'-piperidine]-r-carboxamide (5.2 mg, 12 %). 1H NMR (400MHz, CD3OD): δ=1.61 (s, IH), 1.653 (d, 2H), 1.72 (s, IH), 1.88 (m, 10H), 2.015 (d, 5H), 2.286 (s, 3H), 3.027 (t, 2H), 3.867 (s, IH), 4.088 (d, 4H), 7.044 (t, IH), 7.191 (t, 2H), 8.082 (d, IH); LC-MS(4 min) tR = 1.59 min, m/z = 408(M++!). Example 8 tert-Butyl 9-((2-adamantyl)carbamoyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate
A procedure analogous to that described Example ] was followed using tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate. 1H NMR (CD3OD) δ = 1.45 (s, 9H)5 1.49 (m, 8H), 1.72-2.00 (m, 12H)5 3.40 (m, 8H)5 3.82 (s, IH)5 5.69 (m5 IH); LC-MS(4 min) tR = 2.40 min m/z = 432.
Example 9 tert-Butyl 8-((2-adamantyl)carbamoyl)-258-diazaspiro[4.5]decane-2-carboxylate
A procedure analogous to that described Example 1 was followed using tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate. 1H NMR (CD3OD) δ = 1.46 (s, 9H), 1.58 (m5 6H)5 1.73-2.06 (m, 14H)5 3.20 (s, 2H), 3.25-3.54 (m, 6H)5 3.82 (s, IH); LC-MS(4 min) tR = 2.92 mins m/z = 418.
Example 10 (±)-tert-Butyl 7-((2-adamantyl)carbamoyl)-257-diazaspiro[4.5jdecane-2-carboxylate
A procedure analogous to that described Example 1 was followed using tert-butyl
257-diazaspiro[4.5]decane-2-carboxylate. 1H NMR (CDCl3) δ = 1.44 (s, 9H)5 1.50-1.90 (m, 21H), 3.01-3.42 (m, 8H)5 3.92 (m, IH), 4.79 (m, IH); LC-MS(4 min) tR = 2.25, m/z = 418.
Example 11
1 '-((2-Adamantyl)carbamoyl)spiro[indene- 1 ,4'-ρiperidine]-3-carboxylic acid
A procedure analogous to that described Example 3 was followed using l'-(tert- butoxycarbonyl)spiro[indene-l,4'-piperidine]-3-carboxylic acid in Step 1. 1H NMR (CD3OD) δ = 1.29 (d, 2H)5 1.63 (d, 2H), 1.85 (m, 8H)5 2.00 (m, 4H), 2.13 (m, 2H), 3.25 (m, 2H), 3.89 (s, IH), 4.16 (m, 2H)5 7.26 (m, 2H)3 7.38 (m, IH), 7.85 (s, IH), 7.92 (m, IH)5 LC-MS(4 min) tR = 2.48 min, m/z = 407. Example 12
(±)-r-((2-Adamantyl)carbamoyl)-2,3-dihydrospiro[indene-l,4'-piperidine]-3-carboxylic acid
A procedure analogous to that described Example 3 was followed using 1 '-(tert- butoxycarbonyl)-2,3-dihydrospiro[indene-l,4'-piρeridine]-3-carboxylic acid in Step 1. 1H NMR (CD3OD) δ = 1.54 (m, IH), 1.65 (m, 3H)5 1.82 (m, 9H)3 1.98 (m, 5H), 2.46 (m. 2H), 3.06 (m, 2H)5 3.86 (s, IH)5 4.06 (m, 3H), 7.21 (m5 3H)5 7.39 (m, IH); LC-MS(4 min) tR = 2.44 min, m/z = 409.
Example 13 (±)-r-((2-Adamantyl)carbamoyl)spiro[chroman-2,4'-piperidine]-4-carboxylic acid
A procedure analogous to that described Example 3 was followed using 1 '-(tert- butoxycarbonyl)spiro[chroman-2,4'-piperidine]-4-carboxylic acid in Step 1. 1H NMR (CD3OD) δ = 1.65 (m, 3H), 1.84 (m5 10H), 1.96 (m, 4H), 2.16 (m, IH), 3.15 (m. IH)5 3.36 (m, IH), 3.86 (m, 4H), 6.86 (m, 2H), 7.15 (m, IH), 7.23 (m5 IH) LC-MS(4 min) tR = 2.44 min, m/z = 425.
Example 14
(±)-2-(r-(Cyclohexylcarbamoyl)spiro[chjoman-2.4l-piperidine]-4-yl)acetic acid
A procedure analogous to that described Example 3 was followed using 2-(T- (tert-butoxycarbonyl)spiro[chroman-2,4'-piperidine]-4-yl)acetic acid in Step L 1H NMR (CD3OD) δ = 1.61 (m, 3H), 1.74-1.90 (m, 1 IH)5 1.96 (m, 4H)5 2.05 (m, IH), 2.48 (m,
IH)5 3.00 (m, IH), 3.13 (m, IH), 3.39 (m, 2H)5 3.74 (m, IH)3 3.84 (m, 2H)5 6.84 (m, 2H), 7.08 (m, IHO, 7.23 (m, IH); LC-MS(4 min) tR = 2.52 min, m/z = 439.
Example 15 Ethyl r-((2-adamantyl)carbamoyl)spiro[indene-l,4'-piperidine]-3-carboxylate
A procedure analogous to that described Example 4 was followed using 1 '-((2- adamanty^carbamoyOspirofindene-lΛ'-piperidineJ-S-carboxylic acid and ethanol. 1H NMR (CD3OD) δ = 1.40 (m, 5H)5 1.63 (m, 2H)5 1.84 (m5 8H)5 1.98 (m5 5H)5 2.11 (m, 2H)5 3.25 (m, 2H)5 3.89 (m, IH), 4.15 (m, 2H)5 4.36 (m5 2HO5 7.26 (m5 2H)5 7.39 (m, IH)5 7.84 (s5 IH)5 7.91 (m5 IH); LC-MS(4 min) tR = 2.19 min5 m/z = 435.
Example 16
(±)-Ethyl 1 '-(cyclohexylcarbamoyl^S-dihydrospirotindene- 1 ,4'-piperidine]-3- carboxylate
A procedure analogous to that described Example 4 was followed using 1 '-((2- adamantyl)carbamoyl)-2,3-dihydrospiro[indene-l34'-piperidine]-3-carboxylic acid and ethanol. 1H NMR (CD3OD) δ = 1.29 (t, 3H)5 1.54 (m, IH), 1.64 (m, 2H)5 1.86 (m, 9H)5 1.96 (m, 5H)5 2.43 (m52H)5 3.04 (m, 2H)5 3.86 (s, IH)5 4.06 (m, 2H)5 4.15 (m, IH)5 4.20 (m. IH)5 7.20 (m, 3H), 7.34 (m, IH); LC-MS(4 min) tR = 2.12 min, m/z = 437.
Example 17
(±)-Ethyl r-(cyclohexylcarbamoyl)spiro[chroman-2J4'-piperidine]-4-carboxylate
A procedure analogous to that described Example 4 was followed using 1 '-((2- adamantyl)carbamoyl)spiro[chroman-254'-piperidine]-4-carboxylic acid and ethanol. 1H NMR (CD3OD) δ = 1.29 (t5 3H)5 1.60 (m, 3H), 1.70 (m, IH)5 1.83 (m, 9H)5 1.96 (m, 4H)5 2.11 (m5 2H)5 3.14 (m, IH)5 3.48 (m, IH)5 3.80 (m, 3H)5 3.94 (m5 IH), 4.21 (m5 2H)5 6.84 (m, 2H)5 7.16 (m, 2H); LC-MS(4 min) tR = 2.10 min, m/z = 453.
Example 18 (±)-Ethyl 2-(l '-((2-adamantyl)carbamoyl)spiro[chroman-2,4'-piperidine]-4-yl)acetate
A procedure analogous to that described Example 4 was followed using 2-(l'-((2- adamantyl)carbamoyl)spiro[chroman-2,4'-piperidine]-4-yl)acetic acid and ethanol. 1H NMR (CD3OD) δ = 1.24 (t, 3H), 1.50 (m5 IH)5 1.60 (m5 IH)5 1.83 (m, 10H)5 1.97 (m, 3H)5 2.01 (m, 2H)5 2.45 (m, IH), 3.00 (m, IH)5 3.12 (m, IH)5 3.47 (m, 2H)5 3.73 (m, IH), 3.84 (m, 2H)5 4.15 (m, 2H)5 6.84 (m5 2H)5 7.08 (m, IH)5 7.20 (m, IH); LC-MS(4 min) tR = 2.19 min, m/z = 467. Example 19 N-(2-Adamantyl)-l-(methylsulfonyl)spiro[indoline-3,4'-piperidine]-r-carboxamide
A procedure analogous to that described in Example 7 was followed using methanesulfony] chloride. 1H NMR (CD3OD) δ = 1.63 (m, 2H)3 1.75 (m, 2H), 1.83 (m, 9H), 1.98 (m, 5H)3 2.98 (s, 3H), 3.04 (m, IH), 3.86 (s, IH), 3.93 (s, 2H)3 4.16 (d, 2H)3 7.04 (m, IH)3 7.22 (m, 2H), 7.37 (m, IH); LC-MS(4 rain) tR = 1.67 min, m/z = 444.
Example 20 2- Adamantyl spiro[indoline-3,4'-piperidine]-l '-carboxylate
Figure imgf000099_0001
The title compound was prepared from 1-tert-butyl l'-(2 -adamantyl) spiro[indoline-3,4'-piperidine]-l,r-dicarboxylate following a procedure analogous to Example 2. LC-MS Method 4 tR = 2.319 min, m/z = 367.2; 1H NMR (CD3OD) δ = 1.31 (m, IH)3 1.66 (m, 2H), 1.72-1.88 (m. 8H)3 1.96 (m, 4H)5 2.05 (m, 5H), 2.15 (m, IH)5 3.03-3.26 (m3 2H), 3.36 (s, IH), 3.81 (s, 2H), 4.25 (s, 2H), 7.41 (m, 4H).
Example 21 2-Adamantyl 5-fluorospiro[indoline-3.4'-piperidine]-r-carboxyIate
Figure imgf000099_0002
The title compound was prepared from 1-tert-butyl r-(2-adamantyl) 5- fluorospiro[mdoline-3,4'-piperidine]-l,r-dicarboxylate following a procedure analogous to Example 2. LC-MS Method 4 tR = 2.1 1 1 min, m/z = 385.2; 1H NMR (CD3OD) δ = 1.60-1.71 (m, 2H), 1.75-1.85 (m5 8H), 1.90-2.11 (m, 8H), 2.91-3.28 (m, 2H), 3.91 (m, 2H)5 4.25 (s, 2H), 4.85 (m, IH), 7.19-7.25 (m, IH), 7.31-7.38 (m, IH), 7.48-7.51 (m, IH).
Example 22 2-Adamantyl 5-methylspiro[indoline-3 ,4'-piperidine]-l '-carboxylate
Figure imgf000100_0001
The title compound was prepared from 1-tert-butyl 1 '-(2-adamantyl) 5- methylspiro[indoline-3,4'-piperidine]~l J'-dicarboxylate following a procedure analogous to Example 2. LC-MS Method 4 tR = 1.958 min, mlz = 381.2; 1H NMR (CD3OD) δ =
1.66 (m, 4H), 1.75 (m, IH), 1.79 (m, 8H)3 1.90 (d, 2H)5 2.11 (m, 4H), 2.21 (m, IH), 2.32 (m, 3H), 2.95-3.22 (m, 2H), 3.44 (m, 2H), 4.05-4.20 (m, 2H), 6.61 (d, IH)5 6.85 (d, 2H).
Example 23 2-Adamantyl 1 -acetylspiro[indoline-3,4'-piperidine]-l '-carboxylate
A procedure analogous to that described Example 7 was followed using 2- adamantyl spiro[indoline-3,4'-piperidine]-l '-carboxylate. LC-MS Method 5 IR = 2.874 min, m/z = 431.1 ; 1H NMR (CD3OD) δ = 1.68 (m, 5H), 1.74-1.95 (m, 1 IH), 2.06 (m, 5H), 2.32 (s, 3H), 3.13 (br, 2H)5 4.11 (s, 2H), 4.23 (s, 2H), 7.08 (m, IH)5 7.22 (m, 2H), 8.11 (m, IH). Example 24
(±)-2~Adamantyl 3-(2-methoxy-2-oxoethyl)-2,3-dihydrospiro[indene-l ,4'-piperidine]-l '- carboxylate
Figure imgf000101_0001
Step 1
To a solution of (±)-2-(r-(rer/-butoxycarbonyl)-253-dihydrospiro[indene-l,4'- piperidine]-3-yI) acetic acid (200 mg, 0.579 mmol) in methanol (2 mL) was added dropwise SOCl2 (137.43 mg, 1.158 mmol) at 0°C. The above mixture was allowed to stir at rt overnight. LC-MS showed that the starting material was consumed completely. The mixture was evaporated to give (±)-methyl 2-(2.3-dihydrospiro[indene-l,4'- piperidine]-3-yI) acetate (140.8 mg, 94%). 1H NMR (400MHz, CD3OD): δ=l .65 (m, IH), 1.70-1.90 (m, 3H), 2.32 (m, IH)5 2.50 (m, IH), 2.67 (m, IH)3 2.96 (m, IH)5 3.12- 3.30 (m, 2H)5 3.34-3.50 (m, 2H), 2.66 (m, IH)5 3.72 (s, 3H)5 7.24 (m5 4H).
Step 2
To a solution of the 2-adamantyl chloroformate (144.04 mg, 0.671 mmol) and TEA (135.5 mg, 1.342 mmol) in anhydrous CH2Cl2 (2 mL) was added (±)-methyl 2-(2,3- dihydrospiro[indene-l,4'-piperidine]- 3-yl)acetate (174 mg, 0.671 mmol) at 00C in several portions. The above mixture was allowed to stir at rt overnight. LC-MS showed that the starting material was consumed completely. The mixture was evaporated to give a residue, which was purified by preparative HPLC to afford (±) -2-adamantyl 3-(2- methoxy-2-oxoethyl)-2.3-dihydrospiro[indene-l ,4'-piperidine]-l '-carboxylate (101 mg, 34%). 1H NMR (400MHz5 CD3OD): 6=1.48-1.69 (m, 6H), 1.70-2.01 (m, 8H), 2.06-2.12 (m, 5H)5 2.39-2.51 (m5 IH), 2.62-2.73 (m, IH), 2.85-3.21 (m, 3H)5 3.55-3.65 (m5 IH), 3.75 (m, 3H), 4.05-4.20 (m5 2H)5 4.81 (m, IH), 7.18 (m, 4H). Example 25
2-(r-((2-Adamantyloxy)carbonyl)-2,3-dihydrospiro[indene-l,4'-ρiperidine]-3-yl)acetic acid
Figure imgf000102_0001
2-adamantyl-3-(2-methoxy-2-oxoethyl)-2,3 -dihydrospiro [indene- 134'-piperidine] - 1 '-carboxylate (26 mg, 0.06 mmol) was dissolved in MeOH (1 mL) in an ice-water bath. A solution of LiOH-H2O (4.99 mg, 0.1 19 mmol) in water (0.2 mL) was added dropwise and the mixture was stirred for 8 h at it. LC-MS showed that the starting material was consumed completely. The mixture was evaporated to give a residue, which was purified by preparative HPLC to afford 2-(r-((2-adamantyloxy)carbonyl)-2J3- dihydrospiro[indene-l,4'-piperidine]-3-yl)acetic acid (12.2 mg, 48%). 1H NMR (400MHz, CD3OD): δ=0.91 (m, 2H), 1.32 (m, 3H)5 1.53-1.71 (m, 6H), 1.75-1.93(m, 8H), 1.93-2.18 (m, 4H), 2.24 (m, IH), 2.63 (m, IH)5 2.77 (m, IH), 2.96-3.24 (br, 2H), 3.62 (m, IH)3 4.10-4.28 (br, 2H), 4.72 (s, IH), 7.15 (m, 3H), 7.24 (m, IH).
Example 26
(±)-2-Adamantyl 3-(2-(methylamino)-2-oxoethyl)-2,3-dihydrospiro[indene-l,4'- piperidine]- 1 '-carboxylate
Figure imgf000102_0002
(±)-2-Adamantyl 3-(2-methoxy-2-oxoethyl)-2,3-dihydrospiro[indene-l,4'- piperidine]-l'-carboxylate (33 mg, 0.075 mmol) was added to a solution of methylamine in alcohol (2 mL) at 00C. -The above mixture was heated under reflux overnight. LC- MS showed that the starting material was consumed completely. The mixture was evaporated to give a residue, which was purified by preparative HPLC to obtain (±)-2- adamantyl 3-(2-(methylamino)-2-oxoethyl)-2,3-dihydrospiro[indene-l54'-piperidine]-r- carboxylate (12 mg, 37 %). 1H-NMR (400MHz, CD3OD): δ=L52-1.67 (m, 6H), 1.84 (m: 6H), 1.93 (m, 2H)5 2.07 (m, 5H), 2.28 (m, IH), 2.56 (m, IH), 2.77 (m, 4H), 3.12 (br, 2H)5 3.62 (m, IH)5 4.19 (br, 2H)5 7.18 (m, 4H). "
Example 27 N-(2-Adamantyl)-l,3-dihydrospiro[indene-2,3'-piperidine]-r-carboxamide
Figure imgf000103_0001
Step 1
To a solution of 2-aminoadamantane hydrochloride (126 mg, 0.68 mmol) and DIEA (872 mg, 6 mmol) in anhydrous CH2Cl2 (3 mL) was added CDI (120 mg; 0.74 mmol) at 00C and stirred for 1 h at 00C. Then spiro[indene-2,3'-piperidin]-l(3H)-one (136 mg, 0.68 mmol) in anhydrous CH2Cl2 (2 mL) was added dropwise to the above mixture at 00C. The reaction mixture was stirred overnight under nitrogen at rt. The reaction mixture was evaporated to give a residue, which was purified by preparative TLC and then by preparative HPLC to afford N-(2-adamantyl)-l-oxo-l,3- dihydrospiro[indene-2,3'-piperidine]-r-carboxamide (32 mg, 12 %). 1HNMR (CD3OD, 400 MHZ): δ=1.51~1.75 (m, 3H), 1.76-1.81 (m, 4H), 1.82-2.01 (m, HH)5 3.00 (m, 3H)5 3.22 (m5 3H), 3.72 (m, 2H), 4.03 (m, IH), 7.41 (m, IH), 7.53 (m, -IH), 7.71 (m, 2H). Step 2
To a solution of N-(2-adamantyl)-l-oxo-l,3-dihydrospiro[indene-2,3'- piperidine]-r-carboxamide (30 mg, 0.079 mmol) in MeOH (3 mL) was added NaBH4 (12 mg, 0.317 mmol) at 00C under nitrogen. The reaction mixture was stirred for 4 h under N2 at rt. The reaction mixture was evaporated to give a residue, which was purified by preparative HPLC to afford N-(2 -adamantyl)-! -hydroxy- 1.3- dihydrospiro[indene-2,3'-piperidine3-l'-carboxamide (12 mg, 40 %). 1HNMR (CD3OD, 400 MHZ): 5=1.51-1.75 (m, 5 H)5 1.78-1.81 (m, 4H)5 1.82-2.00 (m, 11H), 2.50 (m, IH)5 3.00 (d, IH)5 3.20 (ra5 IH)5 3.55 (m, IH)5 3.65 (m, IH)5 3.81 (s, IH)5 4.75 (s5 IH)5 7.22 (m5 3H), 7.388 (m, IH). Step 3 To a solution of N-(2-adamantyl)-l -hydroxy- 1 ,3-dihydrosρiro[indene-2,3'- piperidine]-l'-carboxamide (20 mg, 0.052 mmol) in ethanol (3 mL) was added Pd(OH)2 (10 mg), then the reaction mixture was stirred for 4 h at rt under a hydrogen atmosphere. The reaction mixture was filtered and the filtrate was evaporated to give a residue, which was purified by preparative HPLC to afford N-(2-adamantyl)-l53-dihydrospiro[indene- 253'-piperiduie]-r-carboxamide (5 mg, 29 %): LC-MS Method 5 tR = 3.057 min, m/z = 365.2; 1H NMR (CD3OD5 400 MHz): δ=1.55 (m5 2H), 1.66 (m, 2H), 1.78 (m, 7H)5 1.84 (m, 7H), 2.69-2.83 (m, 4H)5 3.21 (s, 2H)5 3.45 (m, 2H)5 3.77 (s, IH)5 7.09 (m, 2H), 7.14 (m, 2H).
Example 28
N-(2-Adamantyl)-2.3-dihydrospiro[indene-l,4'-piperidine]-r-carboxamide
The title compound was prepared following a procedure analogous to that described in Example 1 using 2,3-dihydrospiro[indene-l54'-piperidine]. LC-MS Method 5 tR = 1.946 min, m/z = 365; 1H NMR (CD3OD) δ = 1.54 (d, 2H), 1.63 (d, 2H)5 1.72-2.02 (m, 14H), 2.14 (m, 2H)5 2.94 (m5 2H), 3.09 (m, 2H)5 3.87 (m, IH), 4.03 (d, 2H)5 4.61 (s, IH)5 5.79 (m, IH), 7.12-7.20 (m5 4H).
Example 29 Tert-butyl 1 '-((2-adamantyl)carbamoyl)-lH-spiro[isoquinoline-454'-piperidine]-2(3H)- carboxylate
The title compound was prepared following a procedure analogous to that described in Example 1 using tert-butyl lH-spiro[isoquinoline-4,4'-piperidine]-2(3H)- carboxylate. LC-MS Method tR = 3.036 min, m/z = 480.3 ; 1H NMR (CDCl3) δ = 1.49 (S5 9H)5 1.64 (m, 7H)5 1.76 (m, 5H)5 1.86 (m, 7H), 1.95-2.03 (m, 4H), 3.06-3.21 (m, 2H), 3.71 (m, 2H)5 3.91 (m, 2H), 3.99 (S5 IH)5 4.62 (s, 2H)5 4.82 (m, IH), 7.08 (m, IH), 7.19 ■ (m, 2H)5 7.35 (m, IH). Example 30 N-(2-Adamantyl)-2,3-dihyd.ro-lH-spiro[isoquinoline-4,4'-piperidine]-r-carboxamide
The title compound was prepared from tert-butyl r-((2-adamantyl)carbamoyl)- lH-spiro[isoquinoline-4,4'-piperidine]-2(3H)-carboxylate following a procedure analogous to that described in Example 2. LC-MS Method 4 tβ. = 1.741 min. m/z = 380.3; 1HNMR (CDCl3) δ = 1.66-1.79 (m, 7H), 1.79-2.01 (m, HH), 2.17 (m, 2H)5 3.14 (m, 2H)5 3.58 (m, 2H), 3.93 (m, 3H), 4.41 (s, 2H)5 5.86-6.19 (br, 5H), 7.12 (d, IH), 7.32 (m, IH)5 7.44 (m, 2H).
Example 31
2-Acetyl-N-(2-adamantyl)-253-dihydro-lH-spiro[isoquinoline-4J4'-piperidine]-r- carboxamide
The title compound was prepared from N-(2-adamantyl)-2,3-dihydro-lH- spiro[isoquinoline-4,4'-piperidine]-r-carboxamide following a procedure analogous to that described in Example 7. LC-MS Method 4 tR = 2.931 min, m/z = 422.2; 1H NMR (CD3OD) δ = 1.33 (m5 IH), 1.54-1.68 (m, 4H)S 1.86 (m, 10H)3 1.95-2.08 (m, 7H), 2.24 (d, 3H)5 3.19 (m5 2H)5 3.81-3.98 (m, 5H), 7.17-7.24 (m, 3H)5 7.39 (m, IH).
Example 32
Ethyl 3-(r-((2-adamantyl)carbamoyl)-lH-spiro[isoquinoline-454'-piperidihe]-2(3H)- yl)propanoate
Figure imgf000105_0001
To a solution of 2-adamantyl 2,3-dihydro-lH-spiro[isoquinoline-4,4'-piperidine]- r-carboxylate (40 mg5 0.11 mmol) and TEA (37 mg> 0.32 iranol) in CH2Cl2 (2 mL) was dropwise a solution of acrylic acid ethyl ester (13 mg, 0.13 mmol) in CH2CI2 slowly at 00C under nitrogen atmosphere. The mixture was stirred at rt overnight. The mixture was concentrated to give the crude product, which was purified by preparative TLC followed by preparative HPLC to afford ethyl 3-(r-((2-adamantyl)carbamoyl)-lH- spiro[isoquinoline-4,4'-piperidine]-2(3H)-yl)propanoate (4 mg, yield: 7%). LC-MS Method 4 tR = 5.21 min, m/z = 481.3; 1H NMR (CD3OD3 400 MH2): δ=1.25 (m, 4H)5 1.58 (m. 5H), 1.72 (m, 3H), 1.84 (m, 7H), 1.88-2.17 (m, 5H)5 2.53-2.92 (m5 6H)5 2.94- 3.22 (m, 2H)5 3.68 (s, IH)5 4.09-4.17 (m, 4H)5 4.88 (s, IH)5 7.02 (d, IH), 7.10-7.26 (m, 2H), 7.32 (d, IH).
Example 33
3-(r-((2-Adamantyl)carbamoyl)-lH-spiro[isoquinoline-4.4'-piperidine]-2(3H)- yl)propanoic acid
The title compound was prepared using a method analogous to that of Example 6. LC-MS Method 4 tR = 4.78 min5 m/z = 453.3; 1H NMR (CD3OD) δ = 1.72 (m, 2H)5 1.86-1.97 (m, 8H)5 2.01 (m, 2H), 2.04-2.17 (m, 6H), 2.95 (m, 2H)5 3.18 (m, IH), 3.53- 3.61 (m, 3H), 3.73 (s, 2H), 4.22 (m, 2H)5 4.45 (s, 2H)5 7.24 (m, IH), 7.34 (m, IH), 7.46 (m, IH), 7.56 (m, IH).
Example 34
N-(2-Adamantyl)-2-(methylsulfonyl)-2,3-dihydro-lH-spiro[isoquinoline-4,4'- piperidine] - 1 '-carboxamide
Figure imgf000106_0001
A vial, equipped with a flea stir bar, was charged with methanesulfonyl chloride (4.5 μL5 58 μmol), DIEA (15 μL5 90 μmol) and CH2Cl2 (1 mL). A solution of N-(2- adamantyl)-2,3-dihydro-lH-spiro[isoquinolme-4,4'-piperidine]-r-carboxamide (25 mg, 53 μmol) in CH2Cl2 (1 mL) was added and the mixture was stirred overnight. A 10-mL Chem-Elut cartridge was wetted with 5% aq HCl (6 mL) and allowed to stand for 5 min. The reaction mixture was applied to the cartridge and eluted with ether (20 mL). The eluate was evaporated'to dryness and the residue was purified by preparative HPLC to afford N-(2-adamantyl)-2-(methylsulfonyl)-2,3-dihydro-lH-spiro[isoquinoline-454'- piperidineH'-carboxamide (8 mg, 33%). LC-MS Method 1 tR = 1.89 min, m/z = 458; 1H NMR (CDCl3) δ = 1.60-2.15 (18H), 2.92 (s, 3H)5 3.13 (m, 2H), 3.51 (s, 2H)5 3.90 (d, 2H). 3.99 (s, IH), 4.45 (s, 2H), 4.88 (IH)5 7.05-7.40 (4H).
Example 35 Nl'-(2-Adamantyl)-N2-methyl- 1 H-spiro[isoquinoline-4,4'-piperidine]- 1 ',2(3H)- dicarboxamide
Figure imgf000107_0001
A vial was charged with N-(2-adamantyl)-2,3-dihydro-lH-spiro[isoquinoline- 4,4'-piperidine]-r-carboxarnide (15 mg, 40 μmol), i-Pr2NEt (1 1 μL, 60 μmol) and CH2Cl2 (1 mL). Methyl isocyanate (3 μL, 43 μmol) was added and the mixture was stirred overnight at rt. A l 0-mL Chem-Elut cartridge was wetted with 5% aq HCl (6 mL) and allowed to stand for 5 min. The reaction mixture was applied to the cartridge and eluted with ether (20 mL). The eluate was evaporated to dryness and the residue was purified by preparative HPLC to afford Nl '-(2-adamantyl)-N2-methyl-l H- spiro[isoquinoline-4,4'-piperidine]-r,2(3H)-dicarboxamide (7.7 mg, 44%). LC-MS Method 1 tR = 1.77 min, m/z = 437; 1HNMR (CDCl3) δ = 1.60-2.10 (18H), 2.80 (IH), 2.88 (s, 3H), 3.25 (m, 2H), 3.77 (s. 2H), 3.88 (d, 2H), 3.98 (s, IH), 4.52 (s, 2H), 4.87 (IH), 7.05-7.40 (4H).
Example 36
Ethyl r-((2-adamantyl)carbamoyl)-lH-spiro[isoquinoline-4,4'-piperidine]-2(3H)- carboxylate The title compound was prepared following a procedure analogous to that described in Example 35 using ethyl chlorofqrmate instead of methyl isocyanate. LC- MS Method 1 tR = 2.1 min, m/z = 452; 1H NMR (CDCl3) δ = 1.30 (t, 3H)3 1.60-2.10 (18H), 3.20 (m, 2H)3 3.77 (2H), 3.90 (d, 2H), 3.99 (s, IH)5 4.20 (m, 2H), 4.66 (s, 2H)5 4.85 (s, IH), 7.05-7.40 (4H).
Example 37
2-Tert-butyl 1 '-(2-adamantyl) lH-spiro[isoquinoline-4,4'-piperidine]-l',2(3H)- dicarboxylate
Figure imgf000108_0001
Tert-butyl lH-spiro[isoqumoline-4,4'-piperidine] -2(3 H)-carboxy late (199mg, 0.659mmol) and i-Pr2NEt (139 μL, 1.25 equiv.) were dissolved in CH2Cl2 (1 OmL) and stirred for 1.5 h at it. LC-MS showed the reaction was complete. The mixture was diluted with ether (5OmL)5 washed with 3% aq HCl (2 x 15mL), satd aq NaHCO3 (15 mL) and brine (10 mL), and dried over Na2SO4. Filtration and concentration afforded 2- tert-butyl 1 '-(2-adamantyl) lH-spiro[isoquinoline-4,4'-piperidine]-r,2(3H)-dicarboxylate (246 mg, 80.5%) as a white foam-like solid. LC-MS Method 1 tR = 2.59 min, m/z = 503; 1HNMR (CDCl3) δ = 7.34(1, IH)5 7.20(m5 2H), 7.09(d, IH)5 4.88(t, 2H)5 4.62(s, 2H)5 4.16(d5 2H), 3.72(s, IH)5 3.25-3.03(m, 2H)5 1.50(s, 9H).
Example 38 2-Adamantyl 2,3-dihydro-lH-spiro[isoquinoline-4,4'-piperidine]-r-carboxylate
Figure imgf000108_0002
2-Tert-butyl 1 '-(2-adamantyl) lH-spiro[isoquinoline-4,4'-piperidine]-l ',2(3 H)- dicarboxylate (35mg5 0.073mmol) was dissolved in 1:2 TFA/CH2C12 (6mL) and stirred for 30 min at rt. The mixture was concentrated to afford crude 2-adamantyl 2,3-dihydro- lH-spiro[isoquinoline-4,4'-piperidine]-r-carboxylate (29mg, quant). LC-MS Method 1 tR = 1.48 min, m/z = 381; 1H NMR (CD3OD) δ = 7.52(d5 IH), 7.38(t, IH), 7.28(t, IH)3 7.21(d, IH), 4.85(s, IH), 4.38(s, 2H), 4.19(m, 2H), 3.68(s, 2H)5 3.28-3.01(m, 2H).
Example 39
2-Adamantyl 2-(methylsulfonyl)-2,3-dihydro-lH-spiro[isoquinoline-4,4'-piperidine]-r- carboxylate
The title compound was prepared from 2-adamantyl 2,3-dihydro-lH- spiro[isoquinoline-4,4'-piperidine]-r-carboxylate following a procedure analogous to that described in Example 34. LC-MS Method 1 tR = 2.16 min, m/z = 459; 1H NMR (CDCl3) δ = 7.37(d, IH), 7.28(t, IH), 7.21(t, IH), 7.08(d, IH), 4.88(s, IH), 4.45(br s, 2H)5 4.18(d, 2H)5 3.12(br s, 2H)5 2.92(s, 3H).
Example 40
Cr
2-Adamantyl 2-(isopropylsulfonyl)-253-dihydro-lH-spiro[isoquinoline-4,4'-piperidine]- r-carboxylate
The title compound was prepared from 2-adamantyl 2.3-dihydro-lH- spiro[isoquinoline-4,4'-piperidine]-l '-carboxylate following a procedure analogous to that described in Example 34 using isopropylsulfonyl chloride in place of methanesulfonyl chloride. LC-MS Method 1 tR = 2.31 min, m/z = 487; IH NMR
(CDCl3) δ = 7.36(d5 IH)5 7.26(t5 IH), 7.20(t, IH), 7.05(d, IH)5 4.88(s, IH), 4.56(br s, 2H), 4.18(d, 2H)5 4.35(m, IH)5 2.99(m, 4H)5 1.42(d, 6H). Example 41
2- Adamanty 1 2-(5 -cyanopyridin-2-yl)-2 ,3 -dihy dro- 1 H-spiro [isoquinoline-4 ,4'- piperidine]-l '-carboxylate
Figure imgf000110_0001
Crude 2-adamantyl 253-dihydro-lH-spiro[isoquinoline-4,4'-piperidine]-r- carboxylate (21mg, 0.054mmol), 6-chloro-3-pyridine carbonitrile (llmg, 1.5equiv.) and DIEA (20μL, 2equiv.) were dissolved in dry DMF (1.5mL). The mixture was heated in microwave oven for 20 min at 15O0C. The mixture was diluted with ether (1 OmL), ' washed with 3% aq HCl (2 x 4mL), concentrated and purified by preparative HPLC to afford 2-adamantyl 2-(5-cyanopyridm-2-yl)-2,3-dihydro-lH-spiro[isoquinoIine-4,4'- piperidine]-r-carboxylate (9.5 mg, 37%). LC-MS Method 1 tR = 2.48 min, m/z = 483; 1H NMR (CDCI3) δ = 8.67(br s, IH), 8.50(d. IH), 7.76(m, IH), 7.41(dd, IH)5 7.30(m, IH), 7.21 (d, I H), 6.78(m. IH), 4.89(s, IH), 4.73(s, 2H)3 4.13(d, 4H), 3.31(t, 2H).
Example 42
(±)-Ethyl 2-(7-bromo-r-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-l ,4'- piperidine]-3 -yl)acetate
Figure imgf000110_0002
To a solution of ethyl 2-(7-bromo- 1 '-(2-adamaήtylcarbamoyl)spiro[indene- 1 ,4'- piperidine]-3(2H)-ylidene)acetate (4 g, 8 rnmol) in EtOH (50 mL) was added PtO2 (400 mg) at rt under N2. Then the reaction mixture was stirred at rt for 6 h under H2. The reaction mixture was filtered and the filtrate was concentrated to leave crude (±)-ethyl 2- (7-bromo-r-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-l,4'-piperidine]-3- yl)acetate.
Preparative HPLC followed by chiral HPLC afforded the two enantiomers.
Isomer 1 (1.0 g, 25%): 1HNMR (CD3OD): δ = 1.23 (t, 3H), 1.38 (m, 2H)5 1.62 (d, 2H)3 1.72 (m. IH)5 1.78 (m, 8H), 1.95 (m, 4H)5 2.42 (m, 2H), 2.86 (m, IH)5 3.06 (m, 3H), 3.59 (m5 IH)5 3.86 (m, IH)5 4.14 (m5 2H)5 4.18 (m, 2H)5 7.06 (m, IH)5 7.19 (m5 IH)5
7.36 (m5 IH).
Isomer 2 (1.0 g, 25%): 1H NMR (CD3OD): δ = 1.23 (t, 3H), 1.38 (m, 2H)5 1.62 (d, 2H)5 1.72 (m5 IH), 1.78 (m, 8H)5 1.95 (m5 4H), 2.42 (m5 2H), 2.86 (m, IH)5 3.06 (m, 3H), 3.59 (m, IH), 3.86 (m, IH)5 4.14 (m3 2H), 4.18 (m, 2H), 7.06 (m, IH), 7.19 (m, IH)5
7.37 (m5 IH).
The title compound was also prepared from (±)-ethyl 2-(7-bromo-2.3- dihydrospiro[indene-l.,4'-piperidine]-3-yl)acetate following a procedure analogous to that described in Example 66 Step 1. LC-MS Method 5 tR = 1.761 min, m/z = 531.1; 1H NMR (CDCl3) δ = 1.21-1.31 (m, 3H)5 1.40-1.50 (m. 2H)5 1.64-1.80 (m, 7H)5 1.80-1.90 (m, 6H), 1.94 (m, 2H)5 2.35-2.53 (m, 3H), 2.53-2.80 (m, 8H)5 2.80-2.92 (m, 2H), 2.98- 3.19 (m, 3H)5 3.45-3.64 (m, 2H), 3.89-4.01 (m, 3H), 4.20 (m, 2H), 7.05-7.15 (m, 2H)5 7.40 (m, IH).
Example 43
(±)-2-(7-Bromo-r-((2-adamantyl)carbamoyl)-2.3-dihydrospiro[indene-l54'-piperidine]-
3-yl)acetic acid
Figure imgf000111_0001
To a solution of ethyl 2-(7-bromo-l '-((2-adamantyil)carbamoyl)-253- dihydrospiro[indene-l,4'-piperidine]-3-yl)acetate isomer 1 (1.49 g, 3 mmol) in ethanol (15 mL) was added 2 M aq LiOH-H2O (15 mL, 30 mmol) at 00C and the mixture was stirred overnight at it. The reaction mixture was washed with IN aq HCl until pH = 5-6. The combined organic layers were dried over Na2SO4, filtered and concentrated to afford 2-(7-bromo-r-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-l,4'-piperidine]-3- yl)acetic acid isomer 1 (1.27 g, 90%). LC-MS Method 5 tR = 1.435 min, m/z = 503.2; 1H - I ll -
NMR (CDCl3): δ = 1.48-1.57 (m, 2H), 1.68 (m, 3H), 1.69-1.88 (m5 9H), 1.93 (m, 2H)5 2.49-2.52 (m, 2H), 2.63-2.72 (m, IH)5 2.89-3.17 (m, 4H), 3.52-3.67 (m, IH)5 3.89-4.04 (m, 3H)5 4.91 (m5 IH)5 7.03-7.18 (m, 2H), 7.39 (m, IH).
To a solution of ethyl 2-(7-bromo-r-((2-adamantyl)carbamoyl)-2,3- dihydrospiro[indene-l,4'-ρiperidine]-3-yl)acetate, isomer 2 (1.57 g, 3 mmol) in ethanol (15 mL) was added 2 M aq LiOH-H2O (15 mL, 30 mmol) at 00C and the mixture was stirred overnight at rt. The reaction mixture was washed with 1 aq N HCl until pH = 5-6. The combined organic layers were dried over Na2SO4, filtered and concentrated to obtain 2-(7-bromo-r-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-l,4'-piperidine]-3- yl)acetic acid isomer 2 (1.33 g, 90%). LC-MS Method 5 tR = 1.44 min, m/z = 503.1; 1H NMR (CD3OD): δ = 1.19-1.48 (m, 2H), 1.48-1.62 (m, 4H), 1.65-1.95 (m, 12H)5 2.20- 2.66 (m, 3H), 2.70-3.12 (m, 4H), 3.50 (m, 1H),3.7O -4.08 (m, 3H), 4.89 (m, IH)5 6.90- 7.15 (m, 2H), 7.40 (m, IH).
Application of a similar procedure to (±)-ethyl 2-(7-bromo-l'-((2- adamantyl)carbamoyl)-2,3-dihydrospiro[indene- 1 ,4'-piperidine]-3-yl)acetate afforded
(±)-2-(7-bromo-r-((2-adamanryl)carbamoyl)-2,3-dihydrospiro[indene-l,4'-piperidine]-3- yl)acetic acid. LC-MS Method 5 tR = 1.419 min, m/z = 503; 1H NMR (CD3OD) δ = 1.37-1.46 (m, 2H)5 1.60-1.68 (m. 2H)5 1.71-1.80 (m, IH)5 1.82-1.91 (m, 8H), 1.91-2.06 (m, 5H), 2.40-2.50 (m, 2H)5 2.70-2.81 (m, IH)5 2.93 (m, IH), 3.00-3.15 (m, 3H)5 3.56- 3.67 (in, IH)5 3.88 (s, IH), 4.05-4.12 (d, 2H)5 7.11 (m, IH), 7.22 (d, IH)5 7.39 (d, IH).
Example 44
(±)-N-(2-Adamantyl)-3-(2-(methylsulfonamido)-2-oxoethyi)-2,3-dihydrospiro[indene-
1 ,4'-piperidine]-r-carboxamide
Figure imgf000112_0001
To a stirred mixture of (±)-2-(l'-((2-adamantyl)carbamoyl)-2,3- dihydrospiro[indene-l,4l-piperidine]-3-yl)acetic acid (33 mg, 78 μmol), DMAP (14.3 mg, 117 μmol) and EDCHCl (21 mg, 117 μmol) in CH2Cl2 (3 mL) was added methanesulfonamide (7.4 mg, 78 μmol). The mixture was stirred overnight at it. A lO- mL Chem-Elut cartridge was wetted with 5% aq HCl (6 mL) and allowed to stand for -5 min. The reaction mixture was applied to the cartridge and eluted with ether (40 mL). The eluate was evaporated to leave a white solid (34 mg). Preparative HPLC afforded (±)-N-(2-adamantyl)-3-(2-(methylsulfonamido)-2-oxoethyl)-2,3-dihydrospiro[indeπe- l,4'-piperidine]-l'-carboxarnide (25.4 mg, 65%). LC-MS Method 1 tR = 1.85 min, m/z = 500; 1HNMR (CDCl3) δ = 1.45-2.10 (21H), 2.55 (m, 2H)5 3.07 (m, IH)5 3.33 (s5 3H)5 3.77 (m5 2H)5 3.95 (s, IH)5 4.02 (d, IH)5 4.90 (IH), 7.10-7.30 (4H)5 9.70 (IH).
Example 45
(±)-3-(Cyanomethyl)-N-cyclohexyl-2,3-dihydrospiro[indene-l54'-piperidine]-r- carboxamide
Figure imgf000113_0001
A solution of trifluoroacetic anhydride (39 mg, 0.18 mmol) in dioxane (2 mL) was added dropwise to a stirred, ice-cooled solution of (±)-3-(2-amino-2-oxoethyl)-N-(2- adamantyl)-2,3-dihydrospiro[indene-l54'-piperidine]-r-carboxamide (60 mg, 0.14 mmol) and pyridine (63 mg5 0.28 mmol). The reaction mixture was stirred at it overnight. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SCM5 and concentrated. The crude product was purified by preparative TLC to afford (±)-3-(cyanomethyl)-N-cyclohexyl-2,3- dihydrospiro[indene-l,4'-piperidine]-l'-carboxamide (10 mg, 18%). LC-MS Method 5 tR = 1.508 min, m/z = 404.2; 1H NMR (CDCl3) δ = 1.60-1.73 (m5 5H), 1.77-1.82 (m5 5H)5 1.85-1.94 (m, 2H), 2.07-2.14 (m, IH), 2.51-2.62 (m, 3H), 2.71-2.83 (m, IH), 2.98-3.10 (m, 2H), 3.46-3.55 (m5 IH)5 3.82-3.94 (m5 3H)5 7.10-7.15 (m5 IH)5 7.20-7.28 (m, 3H).
Example 46
(±)-3-((lH-Tetrazol-5-yl)methyl)-N-(2-adamantyl)-2,3-dihydrospiro[indene-l,4'- piperidine]- 1 '-carboxamide
Figure imgf000114_0001
To a solution of (±)-3-(cyanomethyl)-N-cyclohexyl-2,3-dlhydrospiro[indene-l>41- piperidme]-r-carboxamide (30 rag, 0.075 mmol) in toluene (2 mL), Me3SnNs (80 mg, 0.375 mmol) was added. The reaction mixture was stirred at 800C overnight. The mixture was concentrated. The crude product was purified by preparative HPLC to afford (±)-3-((l H-tetrazol-5-yl)methyl)-N-(2-adamantyl)-2,3-dihydrospiro[indene-l ,4'- piperidine]-r-carboxamide (15 mg, 45%). LC-MS Method 5 tR = 1.28 min, m/z = 447.3; 1HNMR (CD3OD): δ = 1.62-1.69 (m, 2H), 1.71-1.86 (m, 4H), 1.89-2.24 (m, 13H), 2.56- 2.68 (m5 IH)5 3.09 -3.29 (m, 3H), 3.49 (s, IH). 3.66-3.74 (m, IH), 3.1-3.90 (m, IH), 3.99 (ss IH), 4.09-4.21 (m, 2H), 7.27 (d, IH), 7.30-7.49 (m, 3H).
Example 47
(±)-Ethyl 2-(r-((2-adamantyl)carbamoyl)-7-methyl-2,3-dihydτospiro[indene-l54'- piperidine] -3 -yl)acetate
The title compound was prepared from (±)-ethyl 2-(7-methyl-2,3- dihydrospiro[indene-l,4'-piperidine]-3-yl)acetate following a procedure analogous to that described in Example 53. LC-MS Method 6 tR = 1.301 min, m/z = 465.2; 1H NMR (CDCl3) δ = 1.22-1.34 (m, 3H), 1.48-1.70 (m, 9H), 1.70-1.79 (m, 4H), 1.82 (m5 8H), 1.93 (m, 2H)5 2.00-2.13 (m, IH)5 2.37 (m, IH), 2.47 (s, 3H), 2.53-2.70 (m, 2H), 2.89-3.01 (in, 2H), 3.09 (m, IH), 3.48-3.59 (m, IH), 3.87-4.01 (m, 3H), 4.16-4.22 (m, 2H), 4.98 (br, IH), 6.94-7.02 (m, 2H), 7.13 (m, IH).
Example 48 (±)-2-(r-((2-Adamantyl)carbamoyl)-7-methyl-2,3-dihydrospiro[indene-l,4'-piperidine]-
3-yl)acetic acid
The title compound was prepared from (±)-ethyl 2-(r-((2-adamantyl)carbamoyl)- 7-methyl-253-dihydrospiro[indene-l54'-piperidine]-3-yl)acetate following a procedure analogous to that described in Example 43. LC-MS Method 5 tR = 1.37 min, m/z = 437.3; 1H NMR (CDCl3) δ = 1.45-1.58 (m, 3H), 1.59-1.67 (m, 2H)3 1.67-1.75 (m, 4H)5 1.76-1.84 (m, 6H)3 1.85-1.93 (m, 2H)5 1.98-2.10 (m, IH), 2.37 (s, 3H), 2.40-2.47 (m, IH)5 2.50-2.69 (m5 2H), 2.90-3.13 (m, 3H), 3.47-3.52 (m, IH), 3.80-3.93 (m, 3H)5 5.08- 5.42 (m, 5H)5 6.92-6.98 (m, 2H)5 7.06-7.12 (m5 IH).
Example 49 (±)-Ethyl 2-(r-((2-adamantyl)carbamoyl)-4-methyl-253-dihydrospiro[indene-l,4'- piperidine] -3 -yl)acetate
The title compound was prepared from (±)-ethyl 2-(4-methyl-2,3- dihydrospiro[indene-l34'-piperidine]-3-yl)acetate following a procedure analogous to that described in Example 53. LC-MS"Method 5 tR = 1.741 min, m/z = 465.2; 1H NMR (CDCl3) 5 = 1.19-1.31 (m, 5H), 1.42-1.52 (m, IH)3 1.59-1.69 (m, 3H)3 1.69-1.89 (m, 8H)3 1.93 (m, 4H)3 1.99-2.08 (m, IH)5 2.17-2.29 (m3 2H), 2.32 (s, 3H), 2.84-2.94 (m5 IH)3 2.94-3.11 (m, 2H), 3.71 (m, 2H)3 3.84-3.99 (m, 3H)5 4.13-4.22 (m5 2H), 7.05-7.16 (m, 2H), 7.18 (m, IH).
Example 50 (±)-2-(r-((2-Adamantyl)carbamoyl)-4-methyl-253-dihydrospiro[indene-l34'-piperidine]-
3-yl)acetic acid
The title compound was prepared from (±)-ethyl 2-(r-((2-adamantyl)carbamoyl)- 4-methyl-2,3-dihydrospiro[indene-l,4'-piperidine]-3-yl)acetate following a procedure analogous to that described in Example 43. LC-MS Method 5 tR = 1.413 min, m/z = 437.2; 1H NMR (CDCl3) δ = 1.24 (m, 2H)5 1.44-1.54 (d, IH), 1.59-1.69 (m, 4H)3 1.71- 1.99 (m, 9H), 2.01-2.15 (m, 3H), 2.21-2.29 (m, IH), 2.34 (m, 4H)3 2.92-3.01 (m, IH)3 3.01-3.14 (m, IH)3 3.65-3.79 (m, IH), 3.83-4.01 (m, 3H)3 4.06-4.14 (m, IH)3 6.95-7.07 (m, 2H)3 7.17 (m3 IH).
Example 51
(±)-Ethyl 2-(l '-((2-adamantyl)carbamoyl)-7-chloro-233-dihydrospiro[indene-l ,4'- piperidine] -3 -yl)acetate The title compound was prepared from (±)-ethyl 2-(7-chloro-2.3- dihydrospiro[indene-l,4'-piperidine]-3-yl)acetate following a procedure analogous to that described in Example 53. LC-MS Method 5 tR = 1.701 min, m/z = 485.2; 1H NMR (CD3OD) δ = 1.39 (m, 3H), 1.42 (m. 2H), 1.60-1.73 (m, 3H)3 1.77-2.01 (m, 12H), 2.32 (m, IH)3 2.50 (m, IH)3 2.69 (m, IH)3 2.72-3.08 (m, 4H), 3.58 (m, IH), 3.86 (s3 IH)3 4.05 (m3 2H), 4.15 (m, 2H)3 7.15 (s, 3H).
Example 52 (±)-2-(l '-((2-Adamantyl)carbamoyl)-7-chloro-2.3-dihydrospiro[indene-l ,4'-piperidine]-
3-yl)acetic acid
The title compound was prepared from (±)-ethyl 2-(r-((2-adamantyl)carbamoyl)- 7-chloro-233-dihydrospiro[indene-l ,4'-piperidine]-3-yl)acetate following a procedure analogous to that described in Example 43. LC-MS Method 5 tR = 1.406 min, m/z = 457.2; 1H NMR (CD3OD) 6 = 1.29 (s, 2H)3 1.41-1.52 (m. 2H)3 1.56-1.73 (m3 3H)3 1.73- 1.91 (m, 8H)3 1.92-2.05 (m, 4H)3 2.31-2.50 (m, 2H)3 2.69-2.80 (m, IH)3 2.87-3.00 (m, 3H)3 3.02-3.15 (m, IH)3 3.59 (m3 IH), 3.84 (s3 IH)3 4.01-4.10 (m, 2H)3 7.10-7.19 (m, 3H).
Example 53
(±)-Ethyl 2-(r-((2-adamantyl)carbamoyl)-6-chloro-2,3-dihydrospiro[indene-l 34'- piperidine] -3 -yl) acetate
Figure imgf000116_0001
A solution of 2-aminoadamantane (123 mg, 0.66 mmol)3 CDI (107 mg. 0.66 mmol), DIEA (232 mg, 0.18 mmol) was stirred at 00C for 1 h. Then (±)-ethyl 2-(6- chloro-233-dihydrospiro[indene-l34'-piperidine]-3-yl)acetate (180 mg, 0.60 mmol) was added to the solution and the mixture was stirred at rt overnight. The solvent was removed and the residue was purified by preparative TLC to give (±)-ethyl 2-(l'-((2- adamanty^carbamoy^-ό-chloro^^-dihydrospirofindene-l^'-piperidinej-S-y^acetate (250 mg, 86%). LC-MS Method 6 tR = 1.492 min, m/z = 485.2; 1H NMR (CDCl3): δ = 1.29(t, 3H)3 1.56-1.66 (m, 4H), 1.66-1.80 (m, 6H), 1.85 (m, 5H), 1.93 (m, 2H), 2.04-2.16 (m, IH)5 2.37-2.49 (m, IH), 2.56-2.65 (m, IH)5 2.88-2.92 (m, IH), 3.00-3.20 (m, 2H), 3.55-3.66 (m, IH)5 3.81-3.90 (m, IH), 3.90-4.00 (m, 2H), 4.20 (q, 2H)5 5.26-5.50 (m, 3H), 7.07-7.14 (m5 2H)5 7.19 (m5 IH).
Example 54
(±)-2-(r-((2-Adamantyl)carbamoyl)-6-chloro-253-dihydrospiro[mdene-l,4'-piperidine]-
3-yl)acetic acid
Figure imgf000117_0001
To a solution of (±)-ethyl 2-(r-((2-adamantyl)carbarnoyl)-6-chloro-2,3- dihydrospiro[indene-l,4'-piperidine]-3-yl)acetate (150 mg, 0.3 mmol) in MeOH (3 mL). LiOH (15 mg, 0.6 mmol) was added and the mixture was stirred for 2 h. The solution was concentrated to give the residue, which was purified by prepative HPLC to obtain (±)-2-(r-((2-adamantyl)carbamoyl)-6-chloro-2,3-dihydrospiro[indene-l ,4'-piperidine]-3- yl)acetic acid (10 mg, 7%). LC-MS Method 5 tR = 1.485 min, m/z = 457.2; 1H NMR (CD3OD): δ = 1.59-1.76 (m, 6H), 1.86-1.99 (m, 8H), 1.99-2.19 (m, 6H), 2.48-2.57 (m5 IH)5 2.78 (m5 IH), 2.95 (m, IH)5 3.00-3.09 (m, IH)5 3.1 1-3.23 (m, IH), 3.69 (m, IH), 3.94 (S5 IH)5 4.06-4.19 (m5 2H), 7.26 (m, 3H).
Example 55
(±)-Ethyl 2-(r-((2-adamantyl)carbamoyl)-5-chloro-2,3-dihydrospiro[indene-l ,4'- piperidine] -3 -yl)acetate
The title compound was prepared from (±)-ethyl 2-(5-chloro-2,3- dihydrospiro[indene-l,4'-piperidine]-3-yl)acetate following a procedure analogous to that described in Example 53. LC-MS Method 5 tR = 2.323 min, m/z = 485.2; 1H NMR (CDCl3) δ = 1.29 (t, 3H), 1.54-1.69 (m, 6H), 1.73 (m, 4H), 1.79-1.89 (m, 6H), 1.92 (m, 2H), 2.04-2.16 (m, IH), 2.36-2.47 (m, IH)5 2.56-2.63 (m, IH-), 2.82-2.90 (m, 1H),2.99- 3.19 (m, 2H)3 3.34-3.58 (m, 4H)5 3.60 (m, 2H), 3.81-3.89 (m, IH), 3.94 (m, 2H),4.16- 4.24 (m, 2H), 7.08 (d, IH), 7.13 (s, IH)5 7.22 (d, IH).
Example 56
(±)-2-(r-((2-Adamantyl)carbamoyl)-5-chloro-2,3-dihydrospiro[indene-l,4'-piperidine]-
3-yl)acetic acid
The title compound was prepared from (±)-ethyl 2-(r-((2-adamantyl)carbamoyl)- 5-chloro-2,3-dihydrospiro[indene-l ,4'-piperidine]-3-yl)acetate following a procedure analogous to that described in Example 54. LC-MS Method 5 tR = 1.442 min, m/z = 457.2; 1H NMR (CDCl3) δ = 1.21-1.32 (m, 4H), 1.43 (m, IH), 1.49-1.70 (m, 6H), 1.72- 1.91 (m3 10H), 1.88-2.11 (m, 3H), 2.42-2.51 (m, IH)5 2.64 (m, IH), 2.85-3.11 (m, 4H)5 3.56-3.67 (m, IH), 3.82-4.00 (m, 3H), 4.80-4.91 (m, IH), 6.99-7 '.10 (m, IH), 7.11-7.20 (m; 2H).
Example 57
(±)-2-(r-((2-Adamantyl)carbamoyl)-6-methyl-2,3-dihydrospiro[indene-l,4'-piperidine]-
3-yl)acetic acid
Figure imgf000118_0001
(±)-2-(6-Methyl-2,3-dihydrospiro[indene-l ,4'-piperidine]-3-yl)acetic acid (0.071 mmol), 2-adamantyl isocyanate (14 mg, 1 equiv) and 1-Pr2NEt (37μL, 3equiv.) were dissolved in CH2Cb (3 mL) and put on a shaker for 1 h at rt. The mixture was diluted with EtOAc (10 mL), washed with 3% aq HCl (2 x 4 mL), concentrated and purified by preparative HPLC to afford (±)-2-(l'-((2-adamantyl)carbamoyl)-6-methyl-2,3- dihydrospiro[indene-l,4'-piperidine]-3-yl)acetic acid (20.4 mg, 66% yield). LC-MS Method 1 tR = 1.93 min, m/z = 437; IH NMR (CDC13) 7.05(q, 2H), 6.96(s, IH), 4.94(br s, IH), 3.98(s, 2H), 3.89(d, IH), 3.59(m, IH), 3.10-2.93(m, 3H)5 2.63(dd, IH)5 2.43(dd, IH)5 2.33(s. 3H)5 2.09(td, IH).
Example 58 (±)-2-(r-((2-Adamantyl)carbamoyI)-5-methyl-2,3-dihydrospiro[indene-l54'-piperidine]-
3-yl)acetic acid
The title compound was prepared from (±)-2-(5-methyl-2.3-dihydrospiro[indene- l,4'-piperidine]-3-yl)acetic acid following a procedure analogous to that described in Example 57. LC-MS Method 1 tR = 1.94 min, m/z = 437; 1H NMR (CDCl3) δ = 7.05(s5 2H), 7.00(s, IH)5 4.90(br s, IH). 3.99(s, 2H)5 3.89(d, 2H), 3.61(m, IH), 3.10-2.93(m5 3H), 2.63(dd, IH)5 2.44(dd, IH), 2.33(s, 3H), 2.08(td,lH).
Example 59 (±)-2-(l '-((2-Adamantyl)carbamoyl)-6-methoxy-2.3-dihydrospiro[indene- 1 ,4'-
" piperidine]-3-yl)acetic acid
The title compound was prepared from (±)-2-(6-methoxy-2,3- dihydrospiro[indene-l,4'-piperidine]-3-yl)acetic acid following a procedure analogous to • that described in Example 57. LC-MS Method 1 tR = 1.83 min, m/z = 453; 1H NMR
(CDCl3) δ = 7.05(d, IH), 6.78(dd, IH), 6.73(d, IH), 4.97(br s, IH)3 3.97(s, 2H)3 3.88(d, IH), 3.78(s, 3H), 3.61(m, IH), 3.11-2.92(m, 3H)5 2.62(dd, IH)5 2.46(dd5 IH)5 2.05(td, IH).
Example 60
(±)-2-(l l-((2-Adamantyl)carbamoyl)-6-fluoro-2,3-dihydrospiro [indene- 1 ,4'-piperidine]-
3-yl)acetic acid
The title compound was prepared from (±)-2-(6-fiuoro-2,3-dihydrospiro[indene- l,4'-piρeridine]-3-yl)acetic acid following a procedure analogous to that described in
. Example 57. LC-MS Method ,1 tR = 1.87 min, m/z = 441; 1H NMR (CDCl3) δ = 7.13(dd, IH), 6.90(td, IH), 6.83(dd, IH)5 3.97(m, 2H), 3.90(d, IH), 3.60(m5 IH), 3.14-2.90(m, 3H), 2.65(dd, IH), 2.47(dd, IH), 2.04(td, IH). Example 61 (±)-Ethy 1 2-(7-bromo- 1'-(( 1 -adamantyl)carbamoyl)-2,3 -dihy drospiro [indene- 154'- piperidine] -3 -yl)acetate
The title compound was prepared from (±)-ethyl 2-(7-bromo-2,3- dihydrospiro[indene-l,4'-piperidine]-3-yl)acetate and 1-adamantyl isocyanate following a procedure analogous to that described in Example 57. LC-MS Method 1 tR = 2.32 min, m/z = 531; 1H NMR (CDCl3) δ = 7.38(d, IH), 7.12-7.04(m, 2H), 4.19(q, 2H)5 3.87(m5 2H), 3.57(m, IH)5 3.13-2.83(m, 4H), 2.63(dd5 IH), 2.44(m, 2H), 1.42(d, 2H), 1.29(t, 3H).
Example 62
(±)-2-(7-Bromo-l'-((l -adamantyl)carbamoyl)-2,3-dihydrospiro[indene-l ,4'-piperidine]- 3-yl)acetic acid
The title compound was prepared from (±)-ethyl 2-(7-bromo-l'-((l- adamantyl)carbamoyl)-2,3-dihydrospiro[indene-l ,4'-piperidine]-3-yl)acetate following a procedure analogous to that described in Example 54. LC-MS Method I tR = I .99 min, m/z = 503; 1H NMR (CDCl3) δ = 7.40(d5 IH)5 7.16-7.06(m, 2H), 3.87(m, 2H)5 3.59(m, IH)5 3.17-2.93(m, 4H)3 2.68(dd5 IH)5 2.48(m, 2H), 1.44(d, 2H).
Example 63
(=t)-2-(7-Bromo-r-((2-adamantyloxy)carbonyl)-2:,3-dihydrospiro[indene-l54'- piperidine]-3-yl)acetic acid
Figure imgf000121_0001
Step 1
A 100-mL of flask was charged with (±ytert-butyl 7-bromo-3-(2-ethoxy-2- oxoethyl)-2,3- dihydrospiro[indene-l54'-piperidine]-r-carboxylate (500 mg, 1.1 mmol) dissolved in 20% TFA in CH2Cl2 solution (15 mL) at 00C. The mixture was stirred for 0.5 h at 00C. Then the mixture was concentrated to give crude (±)-ethyl 2-(7-bromo-2.3- dihydrospiro[indene-l,4'-piperidine]-3-yl)acetate which was used in the next step without further purification. Step 2
A 100-mL flask was charged with (±)-ethyl 2-(7-bromo-2,3-dihydrospiro[indene- l,4'-piperidine]-3-yl)acetate (457 mg, 1.3 mmol) dissolved in dry CH2Cl2 (10 mL). TEA (394 mg, 3.9 mmol) was added at 00C and stirred for 1 h. 2-adamantyl chloroformate (301 mg, 1.4 mmol) was added and the mixture was stirred overnight. The mixture was concentrated to give a residue was purified by column chromatography to give (±)-(2- adamantyl) 7-bromo-3-(2-ethoxy-2-oxoethyl)-2,3-dihydrospiro[indene-l,4'-piperidine]- l'-carboxylate (270 mg, 39%). The enantiomers were separated by chiral HPLC to give isomer 1 (100 mg, 14%) and isomer 2 (100 mg, 14%). Step 3 A 25-mL of flask was charged with (2-adamantyl) 7-bromo-3-(2-ethoxy-2- oxoethyl)-253-dihydrospiro[indene-l,4'-piperidine]-r-carboxylate isomer 1 (100 mg, 0.19 mmol) dissolved in MeOH (3 mL). LiOH (10 mg, 0.38 mmol) dissolved in H2O (3 mL) was added and the mixture was stirred for 2 h at rt. The mixture was concentrated to remove MeOH. The aqueous layer was acidified with 1 N aq HCl (5 mL) and extracted with EtOAc (3 x 5 mL). The organic layers were combined, washed with brine, dried over Na2SO4, filtered and concentrated to give 2-(7-bromo-l'-((2- adamantyloxy)carboπyl)-2.3-dihydrospiro[indene-l,4'-piperidine]-3-yl)acetic acid isomer 1 (45 mg3 47%). LC-MS Method 5 tR = 1.604 min, m/z = 504.1; 1H NMR (CD3OD): δ = 1.26 (m, IH), 1.37 (d, 2H)5 1.61-2.09 (m, 15H)5 2.41 (m5 2H)5 2.72 (m, IH)5 1.39 (m5 IH)5 3.01-3.22 (m5 3H)5 3.55 (m, IH)5 4.11-4.29 Qo, 2H)5 7.06 (m, IH)3 7.20 (d, IH), 7.36 (d5 IH).
(2-Adamantyl) 7-bromo-3-(2-ethoxy-2-oxoethyl)-2,3-dihydrospiro[indene-l54'- piperidine]-l'-carboxylate isomer 2 was converted to 2-(7-bromo-l'-((2- -1 adamantyloxy)carbonyl)-253-dihydrospiro[indene-l541-piperidine]-3-yl)acetic acid isomer 2 using a similar procedure. LC-MS Method 5 tR = 1.604 min5 m/z = 502.1; 1H NMR (CD3OD) δ = 1.37 (d5 2H)5 1.62 (d, 3H)5 1.70-1.95 (m5 8H)52.05 (m, 4H)5 2.40 (m, 2H)5 2.70 (m, IH)5 2.87 (m, IH)5 2.92-3.20 (b, 2H)5 3.55 (m, IH)5 4.10-4.30 (b, 2H)5 7.05 (m, IH)5 7.20 (d, IH), 7.35 (d5 IH).
(±)-(2-Adamantyl) 7-bromo-3-(2-ethoxy-2-oxoethyl)-253-dihydrospiro[indene- l54'-piperidine]-l'-carboxylate was converted to (+)-2-(7-bromo-l'-((2- adamantyloxy)carbonyl)-253-dihydrospiro[indene-l54l-piperidine]-3-yl)acetic acid using a similar procedure. LC-MS Method 6 tR = 1.698 min, m/z = 504.1; 1H NMR (CDCl3) δ = 0.81-1.02 (m, 4H)5 1.20-1.46 (m, 4H)5 1.46-1.92 (m, 15H)5 1.92-2.11 (m, 4H)5 2.31- 2.85 (m, 5H)5 2.92-3.19 (m, 3H)5 3.56-3.70 (m, 2H)5 4.15-4.36 (m, 2H), 4.60-4.81 (m, 3H), 4.89 (S5 IH), 7.04-7.15 (ra, 2H), 7.40 (m, IH).
Example 64
(±)-2-(6-Methyl-r-((2-adamantyloxy)carbonyl)-2,3-dihydrospiro[indene-l54'- piperidine]-3-yl)acetic acid
The title compound was prepared from 2-(6-methyl-2,3-dihydrospiro[indene-l ,4'- piperidine]-3-yI)acetic acid and 2-adamantyl chlorofoπnate following a procedure analogous to that described in Example 57. LC-MS Method 1 tR = 2.24 min, m/z = 438; 1H NMR (CDCl3) δ = 7.06(q5 2H)5 6.97(s5 IH), 4.88(s, IH)5 4.20(t, 2H), 3.60(m, IH)5 3.13-2.94(m, 3H)55 2.64(dd, IH)5 2.48(dd, IH)5 2.35(s5 3H).
Example 65
(±)-2-(5-Methyl-r-((2-adamantyloxy)carbonyl)-2,3-dihydrospiro[indene-l54'- piperidine]-3-yl)acetic acid The title compound was prepared from 2-(5-methyl-2,3-dihydrospuO[indene-l,4'- piperidine]-3-yl)acetic acid and 2-adamantyl chloroformate following a procedure analogous to that described in Example 57. LC-MS Method 1 tR = 2.24 min, m/z = 438; 1H NMR (CDCl3) δ = 7.06(τn, 2H), 7.00(s, IH), 4.88(s, IH)3 4.19(t, 2H)5 3.61 (m, IH)3 3.03(m, 3H), 2.64(dd, IH)3 2.48(dd3 IH)5 2.34(s3 3H).
Example 66
2-(7-Bromo-r-((2-adamantyl)carbamoyl)-233-dihydrospiro[indene-l;4'-piperidine]-3- yl)propanoic acid
Figure imgf000123_0001
Step 1
To a solution of (±)-ethyl 2-(7-bromo-2,3-dihydrospiro[indene-l,4'-piperidine]-3- yl)proρanoate (160 mg, 0.906 mmol) in dry CH2Cl2 was added CDI (176 mg, 1.08 mmol) and DIEA (1.16 g, 9.06 mmol) at 00C under N2. The mixture was stirred for 1 h, and 2-adamantanamine hydrochloride (331 mg, 0.906) in CH2Cl2 was added. The reaction mixture was stirred at rt overnight. The solvent was removed under reduced pressure to leave a residue which was purified by preparative TLC to give (±)-ethyl 2-(7- bromo-r-(2-adamantylcarbamoyl)-2,3-dihydrosρiro[indene-l34'-piperidine3-3- yl)propanoate (200 mg, 41%). 1H NMR: (400MHz, CDCl3): 5=1.11 (s, 3H), 1.22 (s. 3H), 1.26 (m, 3H)3 1.45 (m, 2H), 1.52 (m, 3H)5 1.73 (m, 4H), 1.85 (m, 7H)5 1.95 (s, 2H)3 2.44 (m3 2H)S 3.02-3.26 (m, 4H)5 3.79 (m, 2H)5 3.98 (m, 3H)5 4.25 (m, 2H)5 6.93 (m, IH)5 7.01 (m, IH), 7.35 (m, IH). Step 2
To a solution (±)-ethyl 2-(7-bromo-r-(2-adamantylcarbamoyl)-2,3- dihydrospiro[indene-l,4'-piperidine]-3-yl)propanoate (63 mg3 0.122 mmol) in anhydrous MeOH (1 mL) was added LiOH-H2O (10 mg, 0.244 mmol) in H2O (0.1 ml). The reaction mixture was stirred at rt overnight. The mixture was concentrated to give crude product, which was purified by preparative TLC to afford 2-(7-bromo-l'-((2- adamantyl)carbamoyl)-253-dihydrospiro[indene-l 54'-piperidine]-3-yl)propanoic acid. 1H NMR: (400MHz5 CDCl3): δ=1.04 (s, 3H), 1.21 (s. 3H), 1.34-1.43 (m, 2H)5 1.60-1.71 (m, 3H)5 1.76-2.08 (m, 13H)5 2.29-2.40 (m, IH)5 2.51-2.61 (m, IH)5 2.99-3.27 (m, 3H)5 3.89 (m, 2H)5 4.02-4.14 (m5 2H)5 7.01 (m, IH)5 7.21-7.33 (m, 2H).
Example 67
(±)-Ethyl -2-(7-bromo- 1 '-((2-adamantyl)carbamoyl)-2,3-dihydrospiro [indene- 1 ,4'- piperidine]-3-yl)-2-methylpropanoate
The title compound was prepared from (±)-ethyl 2-(7-bromo-2,3- dihydrospiro[indene-l541-piperidine]-3-yl)-2-methylpropanoate following a procedure analogous to that described in Example 66 Step 1. LC-MS Method 5 tR = 1.982 min, m/z = 559.1; 1HNMR (CDCl3) δ = 1.12 (s,3H), 1.23 (s. 3H), 1.27 (m, 3H), 1.45 (m, 2H), 1.57-1.75 (m, 3H)5 1.79 (m, 4H)5 1.89 (m, 7H), 1.95 (s, 2H)5 2.45 (m, 2H), 3.02-3.26 (m, 4H)5 3.80 (m, 2H), 3.92 (m, 3H)5 4.21 (m, 2H)5 6.93 (m, IH)5 7.01 (m5 IH), 7.35 (m, IH).
Example 68
(±)-2-(7-Bromo-r-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-l,4'-piperidine]-
3-yl)-2-methylpropanoic acid
Figure imgf000124_0001
Step 1
To a solution of (±)-ethyl 2-(7-bromo-r-((2-adamantyl)carbamoyl)-2.3- dihydrospiro[indene-l,4'-piperidine]-3-yl)-2-meth.ylpropanoate (100 mg, 0.18 mmol) in anhydrous toluene was added DIBAL-H (0.4 mL5 1 M) at -78°C. The mixture was stirred for 30 min and quenched with MeOH. The organic layer was separated, dried and concentrated to give crude (±)-7-bτomo-N-(2-adamantyl)-3-(2-methyl-l-oxopropan-2- yl)-253-dihydrospiro[indene-l54'-piperidine]-r-carboxamide which was used for the next step without purification. Step 2
To a solution of crude (±)-7-bromo-N-(2-adamantyl)-3 -(2 -methyl -1 -oxoρropan- 2-yl)-2,3-dihydrospiro[indene-l,4'-piperidine]-r-carboxamide (40 mg, 0.0778 mmol) in dry acetone was added H2Cr2O7 (234 mg5 0.8 mmol), and the solution was stirred for 1 h. Treatment of the mixture with NaBH4 and concentration afforded the crude product which was purified by preparative HPLC to give (±)-2-(7-bromo-l'-((2- adamantyl)carbamoyl)-253-dihydrospiro[indene-l,4'-piperidine]-3-yl)-2-methylpropanoic acid (1.55 mg, 5%). LC-MS Method 5 tR = 1.504 mm, m/z = 531; 1H NMR: (400MHz3 CDCl3): 5=1.04 (s, 3H), 1.21 (s. 3H), 1.34-1.43 (m, 2H)3 1.60-1.71 (m, 3H)5 1.76-2.08 (m, 13H), 2.29-2.40 (m, IH), 2.51-2.61 (m, IH), 2.99-3.27 (m, 3H), 3.89 (m, 2H), 4.02- 4.14 (m, 2H), 7.01 (m, IH), 7.21-7.33 (m, 2H).
Example 69
(±)-2-Adamantyl 7-bromo-3-(2-(methylsulfonamido)-2-oxoethyl)-2,3- dihydrospiro[indene-l ,4'-piperidine]-l '-carboxylate
The title compound was prepared from 2-(7-bromo-r-(2-adamantyloxycarbonyl)- 2,3-dihydrospiro[indene-l,4'-piperidine]-3-yl)acetic acid following a procedure analogous to that described in Example 44. LC-MS Method 5 tR = 1.648 min, m/z = 581.1 ; 1H NMR (CD3OD) δ = 1.42 (m, 2H), 1.65 (m, 2H), 1.70-1.88 (m, 8H), 1.88-2.12 (m, 7H), 2.39-2.50 (m, 2H), 2.74 (m, 2H), 2.94 (m, 2H), 2.97-3.15 (m, 4H)5 3.64 (m, 2H), 4.10-4.29 (m, 2H)5 7.10 (m, IH), 7.22 (m, IH)5 7.39 (m, IH).
Example 70 (±)-7-Bromo-N-(2-adamantyl)-3-(2-(methylsulfonamido)-2-oxoethyl)-2,3- dihydrospiro[indene-l ,4'-piperidine]-l '-carboxamide
The title compound was prepared from (±)-2-(7-bromo-l'-((2- adamanty^carbamoyl^^jS-dihydrospirotindene-l^'-piperidineJ-S-y^acetic acid following a procedure analogous to that described in Example 44. LC-MS Method 5 tR = 1.406 min, m/z = 579.9; 1H NMR (CDCl3) δ = 1.24 (m, IH), 1.31-1.44 (m, 4H)5 1.60- 1.79 (m, 7H), 1.84 (m, 7H), 1.91 (m, 2H)5 2.51-2.65 (m, 3H)52.85-2.99 (m, 2H)5 3.00- 3.18 (m, 2H), 3.31 (s, 3H), 3.60-3.74 (m, 2H)5 3.80 (d, IH), 3.92-4.08 (m, 2H)5 4.91 (d, IH), 7.06 (m, IH), 7.13 (d, IH)5 7.38 (d, IH).
Example 71 (=fc)-2-Adamantyl 3 -(2-(dimethylamino)-2-oxoethyl)-2,3-dihydrospiro[indene- 1 ,4'- piperidinej-l'-carboxylate
The title compound was prepared from (±)-2-adamantyl 3-(2-methoxy-2- oxoethyl)-2, 3 -dihydrospiro [indene- 1 ,4 '-piperi dine]- 1 '-carboxylate and dimethylarnine following a procedure analogous to that described in Example 26. LC-MS Method 5 tR = 2.959 min, m/z = 473.2; 1H NMR (CD3OD) δ = 1.56 (m, 6H)5 1.83 (m, 6H)5 1.93 (d, 2H)5 2.04 (m, 5H)5 2.51 (m5 IH)5 2.64 (m, IH)5 2.99 (s5 4H)5 3.08 (s, 4H), 3.65 (m, IH), 4.09- 4.22 (br, 2H)5 7.18 (m5 4H).
Example 72
2-(r-((l-(3,5-Dimethoxybenzylcarbamoyl)4-adamantyloxy)carbonyl)-2,3- dihydrospiro [indene- 1 ,4'-piperidine]-3-yl)acetic acid
Figure imgf000126_0001
Step 1
4-oxoadamantane-l-carboxylic acid (200 mg, 1.03 mol)5 (3,5- dimethoxyphenyl)methanamine (172 mg, 1.03 rnrnol), EDCI (410 mg, 2.06 mmol), and HOBt (280 mg, 2.06 mmol) were dissolved in dry CH2Cl2. DIEA (1.3 g5 10 mmol) was added under nitrogen at 00C and the mixture was stirred overnight at rt. The mixture was washed with water and brine. The organic layer was dried and concentrated to give crude product which was purified by preparative TLC to give N-(3,5-dimethoxybenzyl)-4- oxoadamantane-1-carboxamide (231 mg5 65%). 1H NMR: (400MHz5 CDCl3): δ=1.62 (s5 4H) 1.95-2.25 (m, 13H)5 2.59 (s, 2H), 3.78 (s, 3H), 3.83 (s, 3H)S 4.35 (d, 2H)3 6.05 (s, IH), 6.44 (m, 2H)5 7.15 (d, IH). Step 2
To a solution of N-(355-dimethoxyben2yl)-4-oxoadamantane-l-carboxamide (230 mg, 0.670 mol) in anhydrous CH3OH was added NaBH4 (100 mg, 2.7 mmol) at 00C. The reaction mixture was stirred for 1 h at rt. The solvent was removed under reduced pressure, diluted with CH2Cl2 and washed with water. The organic layer was separated, dried, and concentrated to give N-(3,5-dimethoxybenzyl)-4-hydroxyadamantane-l- carboxamide (230 mg, 100%). 1H NMR: (400MHz3 CDCl3): δ= 1.40 (d, IH), 1.46-1.62 (m, 6H)5 1.70-1.82 (m, 5H), 1.84-1.95 (m, 3H) 2.01-2.14 (m, 2H)3 3.75 (s, 3H), 3.80 (s, 3H)3 3.82 (S5 IH)3 4.29 (d, 2H)3 5.98 (s, IH), 6.40 (m, .2H)5 7.08 (d, IH). Step 3
To a solution of N-(3,5-dimethoxybenzyl)-4-hydroxyadamantane-l-carboxamide (210 mg, 0.608 mmol) and TEA (307 mg, 3.04 mmol) in dry CH2Cl2 was added triphosgene (72 nag, 0.234 mmol) at 00C under N2. The mixture was stirred for 1 h, and (±)-2-(233-dihydrospiro[indene-l,4'-piperidine]-3-yl)acetic acid (130 mg, 0.608 mmol) in CH2Cl2 was added. The reaction mixture was stirred overnight at rt. The solvent was removed under reduced pressure. The residue was diluted with CH2CI2 and then washed with water. The organic layer was dried, filtered and concentrated to afford crude product, which was purified by preparative TLC to give 2-(l '-((l-(3,5- dimethoxybenzylcarbamoyl)4-adamantyloxy)carbonyl)-2,3 -dihydrospiro [indene- 1 ,4'- piperidine]-3-yl)acetic acid (50 mg3 14%). LC-MS Method 5 tR = 1.341 min, m/z = 617.1; 1H NMR: (400MHz, CDCl3): δ= 1.22-1.51 (m, 5H)3 1.63 (s, 3H)3 1.75-1.96 (m, 12H)3 2.08 (m, 3H)5 2.22-2.38 (m, 3H)3 2.60-3.12 (m, 12H)D3.41 (s, 2H)3 3.58-3.82 (m3 6H)3 4.00 (m, 2H), 4.33 (d, .2H)3 4.74 (d, IH), 6.11 (d, IH), 6.30-6.50 (m, 2H), 6.96-7.15 (m, 4H).
Example 73
2-(r-((l-Carbamoyl-4adamantyloxy)carbonyl)-233-dihydrospiro[indene-l34'-piperidine]- 3-yl)acetic acid
Figure imgf000128_0001
To a solution of 2-(r-((l-(3s5-dimethoxybenzylcarbamoyl)4- adamantyloxy)carbonyl)-2,3-dihydrospiro[indene-l ,4'-piperidine]-3-yl)acetic acid (40 mg, 0.096 mmol) was added 50% TFA (2.5 mL) at 00C. The reaction mixture was stirred for 4 h at rt. The TFA was neutralized, and the solution was dried and concentrated to give crude product which was purified by preparative HPLC to give 2- (1 '-((1 -carbamoyl-4adamantyloxy)carbonyl)-2,3-dihydrospiro[indene-l .4'-piperidine]-3- yl)acetic acid (2 mg, 7%). LC-MS Method 4 tR = 2.078 min5 m/z = 467.2; 1H NMR: (400MHz, CDCl3): 6= 0.88 (m, 3H), 1.29 (m, 3H)5 1.52-1.68 (m, 8H), 1.60-1.69 (m, 4H)5 1.78-1.94 (m, 13H)5 1.95-2.10 (m, 9H), 2.19-2.30(m5 3H), 2.46 (m, IH), 2.68 (m, IH), 2.90-3.15 (m, 3H)5 3.65 (m, IH)5 4.12-4.27 (m, 2H)5 4.83-4.91 (m, IH)5 5.65-5.79 (m. IH), 7.15-7.24 (m, 4H).
Example 74
2-(7-Bromo- 1 '-(1 -fiuoro-4-adamantylcarbamoyl)-2,3-dihydrospiro[indene- 1 ,4'- piperidine]-3-yl)acetic acid5 isomers 1 and 2
Figure imgf000129_0001
Step 1
To (±)-tert-buty\ 7-bromo-3-(2-ethoxy-2-oxoethyl)-2,3-dihydrospiro[indene-l ,4'- piperi-dine] -l '-carboxylate isomer 1 (500 mg, 1.10 mmol) was added 20% TFA in CH2Cl2 (25 mL) at 00C. The mixture was stirred for 1 h and concentrated to give (±)- ethyl 2-(7-bromo-2,3-dihydrospiro[indene-l ,4'- piperidine]-3-yl)acetate isomer 1 (498 mg, crude). Step 2 A solution of 4-aminoadamantan-l-ol (628 mg, 3.76 mmol) in dry CH2Cl2 (2 mL) was added CDI (736 mg, 4.52 mmol) and DIEA (3.24 g, 25.12 mmol) at 00C under N2 and the mixture was stirred for 1 h. Ethyl 2-(7-bromo-2.3-dihydrospuO[indene-l,4'- piperidine]-3-yl)acetate (1.10 g, 3.14 mmol) was added and the mixture was stirred overnight. The mixture was washed with 5% aq HCl, and the organic layer was concentrated to give the crude product. Purification by preparative TLC followed by preparative HPLC gave two isomers of ethyl 2-(7-bromo-l'-((l-hydroxy-4- adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1.4'-piperidine]-3-yl)acetate. Step S
To a solution of ethyl 2-(7-bromo-r-((l-hydroxy-4-adamantyl)carbamoyl)-2,3- dihydrospiro[indene-l,4'-piperidine]-3-yl)acetate isomer 1 (150 mg, 0.275 mmol) in dry CH2Cl2 (5 mL) was added DAST (0.1 mL) at -78°C. The mixture was stirred for 4 h and quenched with NaHCθ3. The mixture was extracted with CH2Cl2. The organic layer was dried, filtered and concentrated to give the crude product, which was purified by preparative TLC to give ethyl 2-(7-bromo-r-((l-fluoro-4-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-l ,4'-piperidine]-3-yl)acetate isomer 1 (120 mg, 80%). 1H NMR: (400MHz, CDCl3): 5=0.89 (m, 3H)D 1.25 (m, 3H)5 1.43 (m, 2H), 1.61-1.82 (m, 9H), 1.94 (m, 4H), 2.18 (m, IH)5 2.36 (m, 2H), 2.48 (m, 2H), 2.68 (m, IH), 2.85 (m, IH), 2.92-
3.14 (m, 3H), 3.60 (m. IH), 3.88 (m, IH), 3.95 (m5 2H), 4.20 (m, 2H), 4.70 (m, IH), 7.09 (m, 2H), 7.41 (m, IH). Step 4
To a solution of ethyl 2-(7-bromo-r-((l-fluoro-4-adamantyl)carbamoyl)-2,3- dihydrospiro[indene-l,4'-piperidine]-3-yl)acetate isomer 1 (120 mg, 0.22 mmol) in
MeOH (6 mL) was added LiOH-H2O (20 mg, 0.44 mmol) at room temperature and the mixture was stirred overnight. The mixture was concentrated to give a residue which was extracted with EtOAc. The organic layer was dried, filtered and concentrated to give crude product, which was purified by TLC to give 2-(7-bromo-r-(l-fluoro-4- adamantylcarbamoyl)-2,3-dihydrospiro[indene-l,4'-piperidine]-3-yl)acetic acid isomer 1 (100 mg, 88%). LC-MS Method 5 tR = 1.227 min, m/z = 521.1; 1H NMR (CD3OD) δ = 1.39 (m, 2H), 1.65-1.80 (m, 7H), 1.83 (m, 2H), 2.05-2.20 (m, 3H), 2.29 (m, 2H), 2.42 (m, 2H), 2.71 (m, IH). 2.88 (m, IH), 2.90-3.10 (m, 3H), 3.55 (m, IH), 3.70 (s, IH), 4.05 (d, 2H), 7.06 (m, IH), 7.20 (d, IH), 7.35 (d, IH). ■ Isomer 2: 1H NMR: (400MHz, CDCl3): δ = 1.26 (m, 2H), 1.40 (m, 2H), 1.70 (m,
6H)5 1.86 (m, 2H)5 2.12 (m, 3H), 2.22 (m, IH), 2.34 (m, 2H), 2.46 (m, 2H), 2.70 (m, IH), 2.86-3.13 (m, 4H), 3.55 (m, IH), 3.70 (m, IH), 4.05 (m, 2H), 7.06 (m, IH), 7.22 (m, IH), 7.35 (m, IH).
Following procedures analogous to those described in Steps 3 and 4, ethyl 2-(7- bromo-1 '-((1 -hydroxy-4-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-l ,4'- piperidine]-3-yl)acetate was converted to 2-(7-bromo-r-(l-fluoro-4- adamantylcarbamoyl^.S-dihydrospirofmdene-l^'-piperidineJ-S-y^acetic acid isomer 2. LC-MS Method 5 tR = 1.235 min, m/z = 519.1; 1HNMR (CD3OD) δ = 1:29 (m, 2H), 1.40 (m, 2H), 1.61 (m, IH), 1.72-1.92 (m, 5H), 2.10 (m, 3H)5 2.34 (m5 2H)5 2.62 (m, IH)5 2.79 (m, IH)5 2.85-3.05 (m, 3H), 3.49 (m, IH), 3.71 (s, IH), 3.97 (d, 2H)5 7.00 (m, .1H), 7.12 (d, IH)5 7.27 (d, IH). Following procedures analogous to those described in Steps 1 to 4 but without separation of the isomers in Step 2, tert-buty\ 7-bromo-3-(2-ethoxy-2-oxoethyl)-2,3- dihydrospiro[indene-l,4'-piperi-dine] -1 '-carboxylate isomer 2 was converted to a mixture of 2-(7-bromo-l '-(1 -fluoro-4-adamantylcarbamoyl)-2,3-dihydrospiro[indene- l,4'-piperidine]-3-yl)acetic acid isomers 3 and 4. LC-MS Method 4 tR = 2.347 mm, m/z = 519.2; 1H NMR (CDCI3) δ = 1.46 (m, 2H), 1.56 (m. IH)5 1.73 (m, 4H)5 1.82 (m5 2H), 1.93 (m, 4H), 2.22-2.32 (m, 3H), 2.51 (m, 2H)5 2.71 (m5 IH)5 2.96 (d, IH)5 3.1 1 (d, IH)5 3.62 (m, IH), 3.83 (m, IH), 3.96 (m, 3H), 7.09 (m, IH)5 7.15 (m, IH), 7.41 (m, IH).
Example 75 2-(7-Bromo-l '-(1 -hydroxy-4-adamantylcarbamoyl)-253-dihydrospiro[indene-l ,4'- piperidine]-3-yl)acetic acid
A mixture of isomers 1 and 2 of the title compound was prepared from a mixture of isomers 1 and 2 of ethyl 2-(7-bromo-r-((l-hydroxy-4-adamantyl)carbamoyl)-2,3- dihydrospiro[indene-l 54'-piperidine]-3-yl)acetate following a procedure analogous to that described in Example 66 Step 2. LC-MS Method 4 tR = 1.972/1.997 min, m/z = 517.1 ; 1H NMR (CDCl3) δ = 1.22. (m, 2H), 1.36 (m. 2H), 1.43 (m, IH), 1.52 (m, 2H)5 1.65 (m, 5H)5 1.82 (m, 2H)5 2.07 (m, 3H), 2.33-2.42 (m, 2H)5 2.61 (m, IH)5 2.88 (m, 2H)5 2.98 (m, 2H), 3.42 (s, 2H), 3.51 (m, IH), 3.82-3.89 (m, 2H)5 7.01 (m, IH), 7.06 (m, IH)5 7.29 (m, IH).
Isomer 3 and 4 of the title compound were prepared from a mixture of isomers 3 and 4 of ethyl 2-(7-bromo-r-((l-hydroxy-4-adamantyl)carbamoyl)-2,3- dihydrospiro[indene-l54'-piperidine]-3-yl)acetate and separated by preparative HPLC. Isomer 3: LC-MS Method 4 tR = 1.972 min, m/z = 519; 1H NMR (CDCl3) δ = 1.37-1.45 (m, 2H), 1.59-1.79 (m. HH), 1.88 (d5 2H)5 2.13 (m, 2H)5 2.21 (s, 2H)5 2.41- 2.52 (m, 2H), 2.63-2.71 (m5 IH)5 2.90-3.19 (m, 4H), 3.56 (m, IH), 3.88-4.00 (m, 3H), 7.03-7.12 (m, 2H),.7.39 (d, IH). Isomer 4: LC-MS Method 4 tR = 2.007 min, m/z = 519; 1H NMR (CDCl3) δ = 1.42-1.56 (m, 4H)5 1.67-1.73 (m. 2H)5 1.75 (m, 6H)5 1.82-1.91 (m, 2H)5 2.16 (m, 3H), 2.44-2.60 (m, 2H), 2.70 (m, IH), 2.92-3.00 (m, IH)5 3.00-3.22 (m, 3H)5 3.58 (m, IH)5 3.82-3.99 (m, 3H), 7.06-7.16 (m, 2H)5 7.40 (d, IH).
Example 76
(±)-2-(7-Bromo-r-(l57-dihydroxy-4-adamantylcarbamoyl)-253-diliydrospiro[indene-l:>4'- piperidine]-3-yl)acetic acid
* The title compound was prepared from 157-dihydroxy-4-aminoadarnantane and (±)-ethyl 2-(7-bromo-2.3-dihydrospiro[indene-l,4'- piperidine]-3-yl)acetate following procedures analogous to those described in Example 74 Steps 2 and 4. LC-MS Method 4 tR = 1.686 min, m/z = 535.1; 1HNMR (CD3OD) δ = 1.37 (s, 3H)5 1.40 (m. 2H)5 1.48 (m, 2H), 1.69 (m, 4H)5 1.75 (m, 2H)5 1.90 (m, 2H)5 2.31 (s, 2H), 2.46 (m, 2H), 2.73 (m, IH)5 2.88(m5 IH)5 2.97 (m5 IH), 3.08 (m, 2H)5 3.58. (m, IH)5 3.65 (s, IH), 4.06 (m, 2H)5 7.09 (m, IH)5 7.23 (m, IH)5 7.36 (m, IH).
Example 77
N-(2-Adamantyl)-6-methoxy-3,4-dihydro-2H-spiro[isoquinoline-l,4'-piperidine]-r- carboxamide
Step 1
A stirred solution of 2-adamantyl isocyanate (0.99 g, 5.6 mmol) in CHaCl2 (40 mL) was cooled in an ice bath and a solution of L5-dioxa-9-azaspiro[5.5]undecane (0.97 g, 6.1 mmol) and DIEA (2.2 mL, 12.3 mmol) in CH2Cl2 (10 mL) was added over 2 min. The ice bath was allowed to melt and the mixture was stirred overnight at rt. The mixture was diluted with ether (150 mL), washed with 5% aq HCl (2 x 50 mL) and satd aq NaHCO3 (50 mL), and dried over MgSO4. Removal of the solvent left N-(2- adamantyl)-l,5-dioxa-9-azaspiro[5.5]undecane-9-carboxarnide (1.55 g, 83%) as a white solid.
Step 2
A stirred mixture ofN-(2-adamantyl)-l,5-dioxa-9-azaspiro[5.5]undecane-9- carboxamide (585 mg, 1.75 mmol), 3-methoxyphenethylamine (0.25 mL, 1.75 mmol) and 85% H3PO4 (5 mL) was heated at 900C for 20 h. The mixture was diluted with water (30 mL) and washed with ether (70 mL). The aqueous layer was basified with NaOH and diluted with water to give a slurry which was extracted with CH2CI2 (2 x 50 mL). The combined CH2Cl2 extracts were washed with brine , dried over Na^SO4 and concentrated to afford an amber oil (780 mg). A 50 mg portion was purified by prep HPLC to afford N-(2-adamantyl)-6-methoxy-354-dihydro-2H-spiro[isoquinoline-l54'- piperi dine] -1 '-carboxamide (13 mg) as an oil. LC-MS Method 1 tR = 1.33 min, m/z = 410; 1H NMR (CDCl3) δ = 1.60-2.30 (20H), 3.10 (2H)5 3.42 (2H)3 3.79 (s, 3H)5 3.92 (2H)5 3.97 (S5 IH)5 5.17 (br s, IH), 6.65 (IH), 6.82 (IH), 7.12 (IH).
Example 78 N-(2- Adamantyl)-3 ,4-dihydro-2H-spiro [naphthalene- 1 ^'-piperidine]- 1 '-carboxamide
The title compound was prepared from 3,4-dihydro-2H-spiro[naphthalene-l54'- piperidine] following a procedure analogous to that described in Example 1. LC-MS Method 5 tR = 1.781 min, m/z - 379.2; 1H NMR (CD3OD) δ = 1.65 (m5 4H)3 1.82 (m, 5H), 1.86 (m, 5H)5 1.95 (m, 6H)5 2.03 (m, 2H), 2.76 (m, 2H)5 3.12 (m, 2H)5 3.87-4.05 (m, 3H), 5.76 (m, IH)5 7.03 (m, 2H)5 7.14 (m, IH), 7.89 (m, IH).
Example 79
(2-Adamantyl) 9-(2-methoxy-2-oxoethyl)-3-azaspiro[5.5]undecane-3-carboxylate
Figure imgf000133_0001
Step 1. Methanol (50 mL) was cooled in an ice bath and SOCl2 (2 mL) was added drop wise with stirring. After 15 min, 2-(3-(tert-butoxycarbon.yl)-3- azaspiro[5.5]undecan-9-yl)acetic acid (0.34 g, purchased from WuXi Pharmatech) was added. The mixture was stirred at rt for 2 d and concentrated to afford methyl 2-(3- azaspiro[5.5]undecan-9-yl)acetate as its hydrochloride salt. Step 2. A vial was charged with methyl 2-(3-azaspiro[5.5]undecan-9-yI)acetate HCl salt
(31 mg, 0.12 mmol) and DIEA (45 μL, 0.25 mmol). A solution of 2-adamantyl chloroformate (25 mg, 0.12 mmol) in CH2CI2 (2 mL) was added and the mixture was stirred overnight at rt. A 10-mL Chem-Elut cartridge was wetted with 5% aq HCl (6 mL) and allowed to stand for 5 min. The reaction mixture was applied to the cartridge and eluted with ether (20 mL). The eluate was evaporated to dryness and the residue was purified by preparative HPLC to afford (2-adamantyl) 9-(2-methoxy-2-oxoethyl)-3- azaspiro[5.5]undecane-3-carboxylate (35 mg, 74%). LC-MS Method 1 tR = 2.52 min. m/z = 404; 1H NMR (CDCl3) δ = 1.05-2.10 (27H), 2.23 (d, 2H), 3.41 (m, 4H)5 3.69 (s, 3H)5 4.82 (s, IH).
Example 80 2-(3-((2-Adamantyl)oxycarbonyl)-3-azaspiro[5.5]undecan-9-yl)acetic acid
Figure imgf000134_0001
(2-Adamantyl) 9-(2-methoxy-2-oxoethyl)-3 -azaspiro[5.5]undecane-3-carboxylate (30 mg, 74 μmol) was dissolved in THF (0.25 mL), water (0.25 mL) and MeOH (0.5 mL) and LiOH1H2O (8 mg, 0.19 mmol) was added. The mixture was stirred at rt for 2 d and TFA (10 mL, 0.14 mmol) was added. The solution was submitted directly to prep HPLC to afford 2-(3-((2-adamantyl)oxycarbonyl)-3-azaspiro[5.5]undecan-9-yl)acetic acid (10.5 mg, 36%). LC-MS Method 1 tR = 2.17 min, m/z = 390; 1H NMR (CDCl3) δ = 1.0-2.05 (27H), 2.27 (d, 2H)5 3.44 (m, 4H), 4.83 (s, IH).
Example 81 Methyl 2-(3-((2-adamantyl)carbamoyl)-3-azaspiro[5.5]undecan-9-yl)acetate The title compound was prepared following a procedure analogous to that described in Example 79 using 2-adamantyl isocyanate in place of 2-adamantyl chloroformate. LC-MS Method 1 tR = 2.15 min, m/z = 403; 1H NMR (CDCl3) δ = 1.05- 2.10 (27H)5 2.24 (d, 2H), 3.30 (m, 4H), 3.42 (s, IH), 3.68 (s, 3H)5 4.93 (s, IH).
Example 82 2-(3-((2-Adamantyl)carbamoyl)-3-azaspiro[5.5]vιndecan-9-yl)acetic acid
The title compound was prepared following a procedure analogous to that described in Example 80. LC-MS Method 1 tR = 1.83 min, m/z = 389; 1H NMR (CDCl3) δ = 1.10-2.00 (29H)5 3.33 (m, 4H), 2.27 (d, 2H), (3.93 (s, IH).
Example 83
N-(2-Adamantyl)-3H-spiro[isobenzofuran- 1 ,4'-piperidine]-l '-carboxamide
The title compound was prepared from 3H-spiro[isobenzofuran-l,4'-piperidine] following a procedure analogous to that described in Example 79 Step 2 using 2- adamantyl isocyanate in place of 2-adamantyl chloroformate. LC-MS Method 1 tR = 2.03 min, m/z = 367; 1H NMR (CDCl3) δ = 1.60-2.00 (18H), 3.29 (m, 2H)5 3.94 (m, 2H)5 3.99 (S5 IH)5 4.95 (IH)5 5.08 (s, 2H), 7.05-7.35 (4H).
Example 84 2-Adamantyl 3H-spiro[isobenzofuran-l54'-piperidine]-l '-carboxylate
The title compound was prepared from 3H-spiro[isobenzofuran- 1 ,4'-piperidine] following a procedure analogous to that described in Example 79. LC-MS Method 1 tR == 2.42 min, m/z = 368; 1H NMR (CDCl3) δ = 1.50-2.10 (18H), 3.24 (m, 2H), 4.19 (m, 2H), 4.88 (s, IH), 5.09 (s, 2H), 7.05-7.35 (4H).
Example 85
1-Tert-butyl l'-(trans-l -carbamoyl-4-adamantyl) spiro[mdoline-3,4'-piperidine]-l,r- dicarboxylate
Figure imgf000136_0001
The title compound was prepared from tert-butyl spiro[indoline-3,4'-piperidine]- 1 -carboxylate and 1 -methoxycarbonyl-4-adamantyl chloroformate following procedures analogous to those described in Example 79 Step 2, Example 80 and Example 127. LC- MS Method 5 tR = 2.467 min, m/z = 410.2; 1H NMR (CD3OD) δ = 1.53-1.72 (m, 16H), 1.79-2.06 (m, 12H), 2.13 (d, 3H), 3.92 (s, 2H)5 4.18 (m, 2H)3 6.98 (m, IH)5 7.16 (m, 2H), 7.42-7.98 (br, IH).
Example 86 N-(2- Adamantyl)-2-methylspiro[isoindoline- 1 ,4' -piperdine] - r -carboxamide
The title compound was prepared following procedures analogous to those described in Example 87 using 2-methylspiro[isoindoline-l,4'-piperidine]-3-thione in place of spiro[isoindoline-l54'-piperidine]-3-thione in Step 1. LC-MS Method 1 tR = 1.26 min. m/z = 380; 1H NMR (CD3OD) δ = 7.68 (m, IH), 7.47 (m, 3H), 3.00 (s, 3H), 2.26 (m, 2H)5 1.64 (d, 2H).
Example 87 N-(2- Adamantyl)spiro [isoindoline-1 ,4" -piperidine] - 1 " -carboxamide
Figure imgf000136_0002
Step 1
Crude spiro[isoindoline-l54'-piperidine]-3-thione TFA salt was taken up in 1 :1 MeCN: 10% aq K2CO3 (10 mL) and 2-adamantylisocyanate (52 mg, 0.30 rαmol, 2.5 equiv) was added. After 2h the desired thiolactam urea was formed. The mixture was concentrated to ~50% of its original volume and diluted with EtOAc. The mixture was washed with 1.0 M aq HCl and brine, dried OVCrNa2SO4, and evaporated. The residue was purified by flash chromatography on silica (4 g), eluting with 20-80% EtOAc in hexanes, affording N-(2-adamantyl)-3 -thioxospiro[isoindoline- 1 ,4'-piperidine] - 1'- carboxamide (51 mg, 0.093 mmol, 85% yield) as a pale yellow solid. Step 2
N-(2-adamantyl)-3-thioxospiro[isoindoline-l,4'-piperidine]-r-carboxamide (6 mg, 0.015 mg, 1.0 equiv) and Raney Nickel (~1 OOmg) were heated at 600C in ethanol (10 mL) for 0.5 h. After this time LC-MS showed complete reduction of the thiolactam. The mixture was cooled to rt. filtered and evaporated. The residue was purified by prep HPLC to afford N-(2-adamantyl)spiro[isoindoline-l,4'-piperidine]-r-carboxamide as its TFA salt. LC-MS Method 1 tR = 1.28 min, m/z = 366; 1H NMR (CD3OD) δ = 7.45 (m, 3H), 4.14 (m, 2H), 2.20 (m, 2H), 1.64 (d, 2H).
Example 88 7-Chloro-N-(2-adamantyl)-2-methylspiro[isoindoline-l ,4' -piperidine]- 1 " -carboxamide
2-adamantyl-NCO
Figure imgf000137_0001
Figure imgf000137_0002
Step 1
7-Chloro-2-methylspiro[isoindoline-l,4'-piperidine]-3-thione TFA salt (0.628 nimol, 1.0 equiv) was dissolved in 1:1 AcCN:10% aq K2CO3 (10 mL). To this solution 2-adamantyl isocyanate (140 mg, 0.786 mmol, 1.25 equiv) was added and the mixture stirred for 2 h. After this time the desired urea was formed. The mixture was concentrated to ~50% of its original volume and diluted with EtOAc. The mixture was washed with 1.0 M aq HCl and brine, dried over Na2SO4, and evaporated. The residue was purified by flash chromatography on silica (12 g), eluting with 20-80% EtOAc in hexanes, affording 7-chloro-N-(2-adamantyl)-2-methyl-3-thioxospiro[isoindoline- 1 ,4'- piperidine]-r-carboxamide (217 mg, 78% yield) as a pale yellow solid. Step 2
7-Chloro-N-(2-adamantyl)-2-methyl-3-thioxospiro[isoindoline-l,4'-piperidine]- r-carboxamide (21 mg, 0.038 mmol, 1.0 equiv) was dissolved in CH2Cl2 (5 mL) and the solution was cooled to 00C. Methyl triflate (145 mg, 100 μL, 0.84 mmol, 23 equiv) was added and the methylation of the thiolactam monitored by LC-MS. To this solution was added NaBH4 (100 mg, 2.6 mmol, ~70 equiv) and the mixture allowed to stir for 0.5 h. After this time LC-MS showed formation of the desired amine. The mixture was diluted with CH2CI? (~10 mL) and quenched by addition of satd aq NH4CI. The layers were separated and the organic layer was dried over Na2SO4, and evaporated. The residue was purified by preparative HPLC to afford 7-Chloro-N-(2-adamantyl)-2- methylspiro[isoindoline-l,4'-piperidine]-l '-carboxamide as its TFA salt. LC-MS
Method 1 tR - 1.35 min. m/z = 414; 1H NMR (CD3OD) δ = 7.4 (m, 3H)5 3.87 (m, IH), 3.11 (s, 3H)5
Example 89 2-( 1 '-(( 1 -(Benzylcarbamoyl)-4-adamantyloxy)carbonyl)-2,3 -dihydrospiro [indene- 1 ,4'- piperidine]-3-yl)acetic acid
The title compound was prepared following procedures analogous to those described in Example 72 using benzylamine in Step 1. LC-MS Method 5 tR = 1.317 min, m/z = 557.1; 1HNMR (CDCl3) δ = 1.23-1.61 (m, 7H), 1.67 (m. 2H), 1.76-2.03 (m, 9H), 2.18 (m, 4H), 2.29-2.61 (m,9H), 2.61-2.93 (m, 3H), 3.06 (m, IH), 3.48 (s, 2H), 3.97 (m, 2H), 4.23-4.45 (m,2H), 4.73 (m, IH). 6.05-6.26 (d, 2H), 7.02 (m, 3H), 7.06-7.29 (m, 4H), 7.34 (m, 2H). Example 90 4-(l '-(2-Adamantylcarbamoyl)spiro[indoline-3;4'-piperidine]-l -yl)-4-oxobutanoic acid
Figure imgf000139_0001
To a solution of N-(2-adamantyl)spiro[indoline-354'-piperidine]-r-carboxamide (20 mg, 0.06 mmol) and succinic anhydride (12 mg, 0.12 mmol) in CH2Cl2 (5 mL) was added TEA. After stirred for 2 h at rt the solvent was removed to give 4-(l'-(2- adamantylcarbamoyl)spiro[indoline-3,4'-piperidine]-l-yl)-4-oxobutanoic acid (20 mg, 74%). LC-MS Method 5 tR = 3.6 min, m/z = 953.1 ; 1H NMR (CD3OD) δ = 1.69 (d5 2H)3 1.75 (d, 2H)5 1.80-1.99 (m, 1 IH), 2.00-2.10 (m, 5H), 2.20 (s5 2H), 2.60-2.70 (m5 2H)5 2.80-2.90 (m, 2H), 3.06-3.18 (m, 2H), 3.93 (s, IH), 4.10-4.19 (m, 2H), 4.20 (s, 2H)5 5.90 (d, IH)5 7.10 (m5 IH)5 7.19-7.28 (m, 2H)5 8.16 (d5 IH).
Example 91 (E)-4-(r-(2-Adamantylcarbamoyl)-lH-spiro[isoquinoline-454'-piperidine]-2(3H)-yl)-4- oxobut-2-enoic acid
The title compound was prepared from N-(2-adamanryl)-253-dihydro-lH- spiro[isoquinoline-4,4'-piperidine]-r-carboxamide and maleic anhydride following a procedure analogous to that described in Example 90. LC-MS Method 1 tR = 1.7 min, m/z = 478; 1H NMR (CDCl3) 1.60-2.20 (18H)5 3.1 1 (m, 2H), 3.58 (s, 2H)5 3.92 (br S5 4H), 4.39 (s, 2H), 5.00 (br S5 IH)5 6.30-7.45 (6H).
Example 92 4-(r-(2-Adamantylcarbamoyl)-lH-spiro[isoquiiioline-4,4'-piperidine]-2(3H)-yl)-4- oxobutanoic acid
The title compound was prepared from N-(2-adamantyl)-2,3-dihydro-lH- spiro[isoquinoline-4,4'-piperidine]-r-carboxamide following a procedure analogous to that described in Example 90. LC-MS Method 5 tR = 2.055 min, m/z = 480.2; 1H NMR (CD3OD) δ = 1.56-1.70 (m, 4H)5 1.74-1.88 (m, 8H), 1.84-2.08 (m. 6H), 2.65 (m, 2H), 2.76 (m, 2H)5 3.15-3.24 (m, 2H)5 3.84 (m, 2H), 3.92 (s, 2H), 4.01 (m, IH)5 7.16-7.29 (m, 3H), 7.41 (m, IH).
Example 93 5-(r-(2-Adamantylcarbamoyl)spiro[indoline-3,4'-piperidine]-l-yl)-5-oxopentanoic acid
The title compound was prepared from glutaric anhydride following a procedure analogous to that described in Example 90. LC-MS Method 4 tR = 2.341 min, m/z = 480.3; 1H NMR (CDCl3) δ = 1.62 (m, 4H), 1.69 (m, 6H), 1.79 (m5 6H), 1.88 (m, 3H), 2.05 (m, 4H)5 2.51 (m, 4H)5 2.95 (m5 2H)5 3.87 (m, IH), 3.91 (m, 2H), 3.94 (m, IH), 7!02 (m, IH), 7.09 (m, IH)5 7.19 (m, IH)5 7. 24 (m, IH)5 8.16 (m, IH).
Example 94
4-(r-(2-Adamantyloxycarbonyl)-lH-spiro[isoquinoline-4,4'-piperidine]-2(3H)-yl)-4- oxobutanoic acid
The title compound was prepared from N-(2-adamantyl)-2,3-dihydro-lH- spiro[isoquinoline-4.4'-piperidine]-r-carboxamide following a procedure analogous to that described in Example 90. LC-MS Method 1 tR = 1.95 min, m/z = 480; 1H NMR (CD3OD) δ = 7.38(m, IH), 7.26-7.13(m, 3H)5 4.81 (s, 2H), 4.09(m5 2H), 3.85(m, IH), 3.23(m, IH), 2.77(m, 2H)5 2.65(m, 2H).
Example 95
5-(r-(2-Adamantylcarbamoyl)-lH-spiro[isoquinoline-454'-piperidine]-2(3H)-yl)-5- oxopentanoic acid
The title compound was prepared from N-(2-adamantyl)-253-dihydro-lH- spiro[isoquinoline-4,4'-piperidine]-r-carboxamide and glutaric anhydride following a procedure analogous to that described in Example 90. LC-MS Method 5 tR = 2.034 min, m/z = 494.3; 1H NMR (CD3OD) δ = 1.52-1.69 (m, 4H)5 1.79-2.04 (m, 16H), 2.41 (m, 2H), 2.62 (m, 2H)5 3.16-3.27 (m, 2H)5 3.86 (m, 2H), 3.98 (m, 3H)5 7.15-7.39 (m5 3H), 7.41 (d, IH).
Example 96 5-(r-(2-Adamantylcarbamoyl)spiro[indoline-3,4'-piperidine]-l-yl)-353-dimethyl-5- oxopentanoic acid
The title compound was prepared from 353-dimethylglutaric anhydride following a procedure analogous to that described in Example 90. LC-MS Method 4 IR = 2.815 min, m/z = 508.3; 1H NMR (CDCl3) δ = 1.18 (s, 6H)5 1.64 (m, 6H), 1.73 (m, 8H)5 1.86 (m, 8H)5 1.95 (m, 10H)5 2.55 (s, 2H)5 2.66 (s, 2H)5 3.01 (m, 2H), 4.00 (m, 2H), 4.05 (s, 3H)54.92 (S5 IH), 7.19 (m, 2H), 7.31 (m, 2H)5 8.29 (m5 IH).
Example 97
4-(r-(2-Adamantylcarbamoyl)-lH-spiro[isoquinoline-4,4'-piperidine]-2(3H)-yl)-2,2- dimethyl-4-oxobutanoic acid
Figure imgf000141_0001
A vialwas charged with 3,3-dimethylsuccinic anhydride (7.4 mg, 58 μmol), DIEA (15 mL, 90 μmol) and CH2Cl2 (1 mL). A solution of N-(2-adamantyl)-253- dihydro-lH-spiro[isoquinoline-454'-piperidine]-r-carboxamide (25 mg, 53 μmol) in CH2Cl2 (1 mL) was added and the mixture was stirred overnight. A 10-mL Chem-Elut cartridge was wetted with 5% aq HCl (6 mL) and allowed to stand for 5 min. The reaction mixture was applied to the cartridge and eluted with ether (20 mL). The eluate was evaporated to dryness and the residue was purified by preparative HPLC to afford 4- (r-(2-adamantylcarbamoyl)-lH-spiro[isoquinoline-4,4'-piperidine]-2(3H)-yI)-252- dimethyl-4-oxobutanoic acid (17 mg, 63%). LC-MS Method 1 tR = 1.87 min, m/z = 508; 1H NMR (CDCl3) 1.32 (s, 6H)5 1.50-2.10 (18H), 2.73 (s, 2H)5 3.20 (m, 2H), 3.90 (m, 4H), 3.94 (S5 IH)3 4.70 (s, 2H)5 4.98 (IH)5 7.05-7.40 (4H).
Example 98 5-(r-(2-Adamantylcarbamoyl)-lH-spiro[isoquinoline-4:>4'-piperidine]-2(3H)-yl)-333- dimethyl-5-oxopentanoic acid
The title compound was prepared from N-(2-adamantyl)-2,3-dirrydro-lH- spiro[isoquinoline-4,4'-piperidine]-r-carboxamide and 3,3-dimethylglutaric anhydride following a procedure analogous to that described in Example 99. LC-MS Method 5 tR = 2.508 min, m/z = 522.3; 1H NMR (CD3OD) δ = 1.10-1.20 (m, 6H), 1.53-1.70 (m. 4H)5 1.77-1.90 (m, 8H)5 1.90-2.06 (m, 6H)5 2.40-2.50 (m, 2H)5 2.64-2.72 (m, 2H)5 3.21 (m5 IH), 3.89 (s, IH), 3.91-4.04 (m, 3H)5 7.13-7.29 (m, 3H)5 7.40 (d, IH).
Example 99
(lS52R)-2-(r-(2-Adamantylcarbamoyl)-2,3-dihydro-lH-spiro[isoquinoline-454'- piperidine]-2-ylcarbonyl)cyclopropanecarboxylic acid
The title compound was prepared from N-(2-adamantyl)-2,3-dihydro-lH- spiro[isoquinoline-4,4'-piperidine]-r-carboxamide and 3-oxabicyclo[3.1.0Jhexane-2,4- dione following a procedure analogous to that described in Example 99. LC-MS Method 1 tR = 1.7 min, m/z = 492; 1H NMR (CDCl3) δ = 1.45-2.35 (21H)5 3.09 (m, 2H)5 3.77 (d, IH)5 3.82 (d, IH), 3.94 (s, 2H)5 4.10 (d5 IH)3 4.79 (m, IH)5 4.88 (s, 2H)5 4.96 (IH)5 7.05- 7.40 (4H).
Example 100
(lRS,2RS)-2-(r-(2-Adamantyloxycarbonyl)-253-dihydro-lH-spiro[isoquinoline-454'- piperidine]-2-ylcarbonyl)cyclopropanecarboxylic acid
Figure imgf000143_0001
Step 1
2-Adamantyl 2,3-dihydro- lH-spiro [isoquinoline-454'-piperidine] -1 '-carboxylate (12 mg, 0.025 mmol), trans-2-(ethoxycarbonyl)cyclopropanecarboxylic acid (8 mg, 2.5 equiv), HATU (11 mg, 1.15 equiv), DIEA (13 μL, 3 equiv) were mixed with CH2Cl2 (2 mL) and put on shaker for 1 h at rt. The mixture was diluted with EtOAc (8 mL), washed with 3% aq HCl (2 x 3mL), concentrated and purified by preparative HPLC to afford 2-adamantyl 2-((lR,2R)-2-(ethoxycarbonyl)cyclopropanecarbonyl)-2,3-dihydro- lH-spiro[isoquinoline-4,4'-piperidine]-l '-carboxylate (9 mg, 69%). Step 2
2-Adamantyl 2-((lRS.2RS)-2-(ethoxycarbonyl)cyclopropanecarbonyl)-2,3- dihydro-lH-spiro[isoquinoline-454'-piperidine]-r-carboxylate (9mg, 0.017mmol) was mixed with 2N aq LiOH (200 μL, excess) and acetonitrile (3 mL). The mixture was stirred overnight at rt. LC-MS showed the reaction was complete. The mixture was concentrated, acidified with 5% aq HCl and extracted with EtOAc (3 x 3 mL). The combined organic layers were concentrated and purified by preparative HPLC to afford ( 1 RS,2RS)-2-(l '-(2-adamantyIoxycarbonyl)-2 ,3 -dihydro- 1 H-spiro [isoquinoline-4,41- piperidine]-2-ylcarbonyl)cyclopropanecarboxylic acid (4.6 mg, 54%). LC-MS Method 1 tR = 1.98 min, m/z = 493; 1H NMR (CDCl3) δ = 7.37(1, IH), 7.31-7.19(m, 2H), 7.13(d, IH), 4.89(m, 3H), 4.16(m, 3H), 3.15(m, 2H), 2.50(m, IH), 2.29(m, IH).
Example 101.1
Ethyl 2-(7-bromo-l'-(2 -adamantylcarbamoyl)spiro[indene-l,4'-piperidine]-3(2H)- ylidene)acetate
Figure imgf000144_0001
To a solution of 2-aminoadamantane hydrochloride (4.17 g, 22 mmol) and DIEA (28.7 g, 223 mmol) in anhydrous CH2Cl2 (40 mL) was added CDI (4.33 g, 27 mmol) at 00C and then stirred for 1 h at 00C under N2 atmosphere. Ethyl 2-(7-bromospiro[indene- 1 ,4'-piperidine]- 3(2H)-ylidene)acetate (7.77 g3 22 mmol) in CH2Cl2 anhydrous (40 mL) was added drop wise to the above mixture. The mixture was stirred for 8 h at rt under N2. The reaction mixture was washed with 1 N aq HCl. The organic layer was dried over Na2SO4, filtered and concentrated to leave a residue, which was purified by silica gel column chromatography to afford ethyl 2-(7-bromo-l '-(2- adamantylcarbamoyl)spiro[indene-l,4'-piperidine]-3(2H)-ylidene)acetate (4.1 g5 35%). Preparative SFC using a ChiralCel-OJ, 400 x 25 mm 1.D9 20 μm (Daicel Chemical Industries, Ltd) column maintained at 35°C eluted with 75:25 supercritical CO2ZMeOH at a flow rate of 70 mL min"1 and a nozzle pressure of 100 bar afforded two isomers. Isomer 1: LC-MS Method 5 tR = 1.799 min, m/z = 529; 1H NMR (CDCl3) δ = 1.22-1.29 (t, 3H)3 1.51-1.70 (m, 10H)5 1.71-1.81 (m, 4H)5 1.82-1.91 (m, 7H)5 1.92-2.03 (m, 2H), 2.95-3.21 (m, 4H)3 3.53 (m, 2H)5 3.98-4.15 (m, 3H)5 4.15-4.24 (m, 2H)5 4.98 (br, IH), 6.91 (s, IH)5 7.02-7.08 (m, IH)5 7.20-7.26 (m, IH)5 7.32-7.36 (m5 IH).
Isomer 2: LC-MS Method 5 tR = 1.9 min, m/z = 529.1; 1H NMR (CDCl3) δ = 1.30-1.38 (m5 4H)5 1.51-1.70 (m, 8H), 1.70-1.81 (m, 4H)5 1.83-1.89 (m, 6H), 1.92-2.01 (m, 2H), 2.78-2.97 (m5 2H), 3.02-3.17 (m, 2H), 3.32 (S5 2H)5 3.96-4.08 (m, 3H)5 4.20- 4.29 (m, 2H)5 4.89-5.01 (br, IH)5 6.33 (s, IH)5 7.12-7.20 (t, IH)5 7.52-7.60 (m, 2H).
Example 102
3-Allyl-7-chloro-N-(2-adamantyl)-3H-spiro[isobenzofuran-l ,4'-piperidine]- 1 '- carboxamide
Figure imgf000144_0002
Step 1.
A solution of ter/-butyl 7-chloro-3-hydroxy-3H-spiro[isobenzofuran-l,4'- piperidine]-l'-carboxylate (0.0175 g, 0.0514 mmol, 1.0 equiv) and allyltrimethylsilane (0.1660 g, 1.45 mmol, 28 equiv) in CH2Cl2 (2 mL) was cooled to -780C. Boron trifluoride diethyl etherate was added dropwise (10 drops, 0.0520 g, 7.1 equiv), and the solution was allowed to stir, coining to ambient temperature, for 16 h. The reaction was then quenched with 1 mL of satd aq K2CO3, diluted with CH2Cl2, and dried over K2CO3. After the solvents were evaporated, the crude 3-allyl-7-chloro-3H-spiro[isobenzofuran- 1 ,4'-piperidine] (0.0190 g) was directly used in the next step without further purification. LC-MS Method 1 tR = 1.18 min, m/z 266, 264 (MH+). Step 2
To a stirred solution of 3-allyl-7-chloro-3/-r-spiro[isobenzofuran-l,4'-piperidine] (0.0190 g), and DIEA (0.5 mL) in CH2Cl2 (2 mL) was added 2-adamantyl isocyanate (0.0138 g, 0.0778 mmol) at rt. After 19 h, the solvents were removed in vacuo and the residue was purified by reversed-phase HPLC (phenomenex® Luna 5μ C 18(2) 100A, 250 x 21.20 mm, 5 micron, 70% -»90% CH3CNZH2O, 0.1% CF3COOH over 8 min and then 90% CH3CNVH2O, 0.1% CF3COOH over 4 min, flow rate 25 mL/min) to afford JV- (2-adamantyl)-3-allyl-7-chloro- 3H-spiro[isobenzpfuran-l,4'-piperidine]-r-carboxamide (0.0220 g, 97%). LC-MS Method 1 ,R = 2.33 min, m/z 4435 441 (MH+); 1H NMR (400 MHz, CDCI3) δ = 7.24-7.20 (m, 2H), 7.09-7.05 (m, IH)5 5.87-5.77 (m, IH), 5.25 (t, J = 5.7 Hz, IH), 5.15-5.08 (m, 2H), 3.98 (br s, IH), 3.94-3.88 (m, 2H), 3.36-3.28 (m, 2H), 2.66-2.38 (m, 4H), 1.95-1.25 (m, 16H).
Example 103 N-(2-AdamantyI)-2,3,3-tiimethylspiro[isoindoline-l,4'-piperidine]-r-carboxamide
Figure imgf000145_0001
The title compound was prepared from 2-methylspiro[isoindoline-l,4'- piperidine]-3-thione following procedures analogous to those described in Example 104 Steps 1 and 2. LC-MS Method 1 tR = 1.33 min, m/z = 408; 1H NMR (CD3OD) δ = 7.81 (d, J = 7.4, IH), 7.50 (m, 3H), 3.00 (s, 3H)3 2.37 (m, 2H), 1.64 (d, 2H).
Example 104
7-Chloro-N-(2-adamantyl)-3,3-dimethylspiro[isoindoline- 1 ,4'-piperidine] -T- carboxamide
Figure imgf000146_0001
PMB = 4-methoxybenzyl
Step 1 To a solution of crude 7-chloro-2-(4-methoxybenzyl)spiro[isoindoline- 1 ,4'- piperidine]-3-thione TFA salt (prepared from TFA deprotection of tert-butyl 7-chloro-2- (4-methoxybenzyl)-3-thioxospiro[isoindoline-l ,4'-piperidine]- 1 '-carboxylate (52 mg, 0.11 mmol)) in 1:1 MeCN: 10% aq K2CO3 (10 mL), was added 2-adamantylisocyanate (50 mg, 0.30 mmol, 2.6 equiv) and the mixture stirred was for 2 h. After this time LC- MS analysis showed formation of the desired urea. The mixture was concentrated to
~50% of its original volume and diluted with EtOAc. The mixture was washed with 1.0 M aq HCl and brine, dried over Na2SO4, and evaporated. The residue was purified by flash chromatography on silica gel (4 g), eluting with 20-80% EtOAc in hexanes, affording 7-chloro-N-(2-adamantyl)-2-(4-methoxybenzyl)-3-tbioxospiro[isoindoline- l,4'-piperidine]-r-carboxamide (51 mg, 0.093 mmol, 85% yield) of the desired thiolactam-urea as a pale yellow solid. Step 2
7-Chloro-N-(2-adamantyl)-2-(4-methoxybenzyl)-3-thioxospiro[isoindoline-l,4'- piperidme]-r-carboxamide (~10 mg, -0.018 mmol, 1.0 equiv) was dissolved in CH2Cl2 (5 mL) and the solution cooled to O0C. Methyl triflate (9 mg, 6 μL, 0.054 mmol, 3.0 equiv) was added and the methylation of the thiolactam was monitored by LC/MS. To this solution was added MeMgBr (3.0 M in THF5 10 equiv, 6 μL) and the mixture allowed to stir for 0.5 h. After this time LC-MS showed formation of the desired amine. The mixture was diluted with CH2CI2 (-10 mL) and quenched by addition of satd aq NH4CI. The layers were separated and the organic layer was dried over Na2SO4, and evaporated to afford crude 7-chloro-N-(2-adamantyl)-2-(4-methoxybenzyl)-3,3- dimethylspiro[isoindoline-l,4'-piperidine]-r-carboxamide which was used without further purification. Step 3 Crude 7-chloro-N-(2-adamantyl)-2-(4-methoxybenzyl)-3,3- dimethylspiro[isomdoline-l,4'-piperidine]-r-carboxamide was dissolved in neat TFA (3 mL) and the mixture was heated to 8O0C for 17 h. After this time LC-MS analysis showed complete removal of the p-methoxybenzyl group. The solution was evaporated the amine purified by prep HPLC to afford 7-chloro-N-(2-adamantyl)-33- dimethylspirofisoindoline- 1 A y -piperidine]- 1 ' -carboxamide as its TFA salt. LC-MS
Method 1 tR = 1.43 min, m/z = 428; 1HNMR (CD3OD) δ = 7.47 (m, 2H), 7.37 (m, IH)5 4.22 (m5 2H)5 3.89 (s, 1H): 3.21 (t, J = 12.9, 2H).
Example 105 7-Chloro-N-(2-adamantyl)-2,3,3-trimethylspiro[isoindoline-l,4'-piperidine]-r- carboxamide
Figure imgf000147_0001
The title compound was prepared from 7-chloro-2-methylspiro[isoindoline-l,4'- piperidine]-3-thione following procedures analogous to those described in Example 104 Steps 1 and 2. LC-MS Method 1 tR = 1.42 min, m/z = 442; 1H NMR (CD3OD) δ = 7.51 (m, 2H)3 7.42 (m, IH)5 3.88 (m, IH)5 3.53 (m5 2H), 3.26 (s, 3H).
Example 106 Methyl 3-(l '-(2-adamantylcarbamoyl)-lH-spiro[isoquinoline-454'-piperidine]-2(3H)- ylsulfonyl)propanoate The title compound was prepared following a procedure analogous to that described in Example 34 using methyl 3-(chlorosulfonyl)propionate in place of MeSO2Cl. LC-MS Method 1 tR = 1.94 min, m/z = 530; 1H NMR (CDCl3) δ = 1.60-2.15 (18H), 2.90 (t, 2H)5 3.13 (m, 2H), 3.39 (t, 2H), 3.57 (s, 2H), 3.75 (s, 3H)5 3.90 (d, 2H)5 3.99 (br s, IH), 4.49 (s, 2H), 4.86 (br S5 IH), 7.05-7.40 (4H).
Example 107
2-Adamantyl 2-(3-methoxy-3-oxopropylsulfonyl)-2,3-dihydro-lH-spiro[isoquinoline- 4,4'-piperidine]- 1 '-carboxylate
The title compound was prepared following a procedure analogous to that described in Example 34 using methyl 3-(chlorosulfonyl)propanoate in place of methanesulfonyl chloride. LC-MS Method 1 tR = 2.22 min, m/z = 531; 1HNMR (CDCl3) δ = 7.36(d, IH), 7.27(t, IH), 7.21(t, IH)5 7.07(d, IH), 4.87(s, IH)5 4.50(br S5 2H), 4.30(br s, 2H)5 4.18(d, 2H), 3.73(s, 3H), 3.37(t, 2H), 3.10(br S5 2H)5 2.90(t, 2H).
Example 108
3-(r-(2-Adamantylcarbamoyl)-lH-spiro[isoquinoline-4,4'-piperidine]-2(3H)- ylsulfonyl)propanoic acid
The title compound was prepared following a procedure analogous to that described in Example 6. LC-MS Method 1 tR = 1.83 min, m/z = 516; 1H NMR (CDCl3) δ = 1.60-2.15 (18H), 2.93 (t, 2H)5 3.15 (m, 2H), 3.42 (t, 2H), 3.57 (s, 2H), 3.90 (d, 2H), 3.97 (br s, IH), 4.52 (s, 2H), 7.00-7.40 (4H).
Example 109 3-(r-(2-Adamantyloxycarbonyl)-lH-spiro[isoquinoline-4.4'-piperidine]-2(3H)- ylsulfonyl)propanoic acid
The title compound was prepared following a procedure analogous to that described in Example 6. LC-MS Method 1 tR = 2.02 min, m/z = 516; 1H NMR (CDCl3) δ = 7.36(d, IH)3 7.26(t, IH), 7.20(t, IH)5 7.06(d, IH), 4.87(s5 IH), 4.49(br d, 2H)5 4.17(d, 2H), 3.74(br s, IH), 3.37(t, 2H), 3.07(br d, IH), 2.94(t, 2H).
Example 110
7-Bromo-N-(2-adamantyl)-3-(2-oxo-2-(piperazin-l-yl)ethyl)-2,3-dihydrospiro[indene-
1 ,4'-piperidine] - 1 '-carboxamide
Figure imgf000149_0001
Step 1.
A DMF (0.2 mL) solution of 1-Boc-piperazine (2.5 mg, 0.013 mmol), carboxylic acid (6 mg, 0.012 mmol), HATU (5.7 mg, 0.015 mmol), and i-Pr2NEt (1 drop) was prepared and allowed to stir for several hours. The solution was diluted with CH3CN (0.3 mL) and purified by preparative HPLC to afford tert-butyl 4-(2-(7-bromo-l'-(2- adamantylcarbamoy^^jS-dihydrospirofindene-l^'-piperidinej-S-y^acety^piperazine-l- carboxylate (6 mg). Step 2. tert-Butyl 4-(2-(7-bromo-r-(2-adamantylcarbamoyl)-2,3-dihydrospiro[indene- l,4'-piperidine]-3-yl)acetyl)piperazine-l-carboxylate (6 mg).was dissolved in CH2CI2 (1 mL) and treated with 20% TFA for 30 min. The solvent was evaporated and the crude material purified by preparative HPLC to afford (±)-7-bromo-N-(2-adamantyl)-3-(2-oxo- 2-(piperazin-l-yl)ethyl)-2,3-dihydrospiro[indene-l,4!-piperidirjie]-r-carboxamide (1.83 mg). LC-MS Method 1 tR = 1.51 min, m/z = 569 (M+l); 1H NMR (CD3OD) δ = 7.37 (d, IH), 7.24 (d, IH), 7.09 m(t, IH), 4.09-4.04 (m, 2H), 3.66-3.62 (m, IH), 2.97 (t, IH), 2.76 (dd, IH), 2.61 (dd, IH), 2.45 (dt, IH), 1.43 (m, 2H). Example 111
7-Bromo-N-(2-adamantyl)-3-(2-morpholino-2-oxoethyl)-2,3-dihydrospiro[indene-l54'- piperidine] - 1 '-carboxamide
The title compound was prepared following the procedure of Example 110 Step 1 using morpholine in place of 1-Boc-piperazine. LC-MS Method 1 tj* = 1.98 min, m/z = 570 (M+l); 1H NMR (CDCl3) δ = 7.38 (d, IH)5 7.12 (d, IH), 7.06 (t, IH)1 4.95 (br s, IH), 4.4-3.98 (m, 2H), 3.89 (dd, IH), 3.72 (3.67 (m, 7H)3 3.48 (m, 2H), 3.15-3.06 (m, 2H), 2.99 (dt, IH)5 2.88 (dd, IH), 2.75 (dd, IH), 2.51-2.42 (m5 2H), 1.94 (br s, 2H), 1.85 (br s, 6H), 1.79-1.57 (m, 7H), 1.422 (ddd, 2H).
Example 1 12 7-Bromo-N-(2-adamantyl)-3-(2-(4-meth.ylpiperazin-l-yl)-2-oxoethyl)-2,3- dihydrospiro[indene-l ,4'-piperidine]- 1 '-carboxamide
The title compound was prepared following the procedure of Example 110 Step 1 using 1-methylpiperazine in place of 1-Boc-piperazine. LC-MS Method 1 tR = 1.52 min, ' m/z = 583 (M+l); 1H NMR (CD3OD) δ = 7.37 (d, IH)5 7.23 (d, IH), 7.09 (t, IH), 4.72 (br s, IH)5 4.24 (br s, IH), 4.06 (m, 2H)5 3.87 (s, IH), 3.66-3.48 (m, 4H), 3.16-3.04 (m, 5H), 2.94 (s, 3H), 2.77 (dd, IH), 2.62 (dd, IH), 2.45 (dt, IH), 2.03-1.79 (m, 12H), 1.70- 1.61 (m, 3H)5 1.40 (t, 2H).
Example 113
N-(2-Adamantyl)-2-(4-(dimethylamino)butanoyl)-2,3-dihydro-lH-spiro[isoquinoline- 4,4'-piperidine]-l '-carboxamide
The title compound was prepared fromN-(2-adamantyl)-2,3-dihydro-lH- spiro[isoquinoline-4,4'-piperidine]-r-carboxarnJde and 4-(dimethylamino)butanoic acid following the procedure of Examplel lO Step 1. LC-MS Method 1 tR = 2.4 min, m/z = 493.38, 1H NMR (CD3OD) δ = 1.55-1.73 (m, 4H)5 1.80-1.94 (m, 8H)5 1.95-2.10 (m, 8H), 2.66-2.72 (m, 2H), 2.82-2.92 (s, 6H), 3.05-3.19 (m, 2H), 3.19-3.28 (m, 2H), 3.80-3.92 (m, IH), 3.92 (s, 3H), 3.93-4.04 (m, IH), 4.72-4.80 (m, 2H), 5.78-5.95 (m, IH)5 7.15- 7.30 (m, 3H), 7.40-7.47 (m, IH). Example 1 14 7-Bromo-N-(2-adamantyl)-3-(2<2-(dimethylainino)ethylainino)-2-oxoethyl)-253- dihy drospiro [indene- 1 ,4'-piperidine] - 1 '-carboxamide
The title compound was prepared following the procedure of Example 110 Step 1 using N,N-dimethylethylenediamine in place of 1-Boc-piperazine. LC-MS Method 1 tR
= 1.51 min, m/z = 571 (M+); IH NMR (CD3OD) δ = 7.38 (d, IH)5 7.19 (d, IH), 7.10 (t,
IH), 4.06 (t, 3H)5 2.96 (s5 6H)5 283 (dd5 2H)5 2.65 (dd, 2H), 2.48 (m, 2H)5 2.37 (dd5 2H)5 1.62 (d5 3H)5 L39 (d, 3H).
Example 115 7-Bromo-N-(2-adamantyl)-3-(2-(methyl(2-(methylamino)ethyl)amino)-2-oxoethyl)-2:,3- dihydrospiro [indene- 154'-piperidine]- 1 '-carboxamide
The title compound was prepared following the procedure *of Example 110 Step 1 using N,N'-dirnethylethylenediamine in place of 1 -Boc-piperazine. LC-MS Method 1 tR = 1-53 min, m/z = 571 (M+); IH NMR (CD3OD) δ = 7.37 (d, IH)5 7.23 (d5 IH)5 7.09 (t, IH)5 4.07 (d, 2H)5 3.87 (br s, IH)5 3.22 (t, 2H)5 3.10 (s, 3H)5 2.75 (s, 3H), 2.59 (dd, IH)5 2.45 (dd, IH), 1.40 (m, 2H).
Using a procedure analogous to that described in Example 1 10 Step I5 2-(7- bromo- 1 '-((2-adamaήtyl)carbamoyl)-253 -dihydrospiro[indene- 1 ,4'-piperidine]-3 -yl)acetic acid, isomer 1 was converted into 7-bromo-N-(2-adamantyl)-3-(2-(methyl(2- (methylamino)ethyl)amino)-2-oxoethy l)-253 -dihydrospiro[indene- 1 ,4'-piperidine] -V- carboxamide, isomer 1. LC-MS Method 5 tR = 1.136 min, m/z = 571.1; 1H NMR (CDCl3) δ = 1.34 (m, 2H), 1.52 (m. IH)5 1.60 (m5 2H)5 1.65 (m5 3H)5 1.78 (m, 6H), 1.86 (m, 2H)5 2.26 (m, 7H)5 2.42 (m5 2H), 2.62 (m, IH), 2.70 (m, 2H), 2.89 (m5 2H), 3.02 (m, 4H), 3.23 (m, IH)5 3.46-3.72 (m, 3H), 3.90 (m, 3H), 4.86 (s, IH), 7.03 (m, 2H), 7.31 (m, IH).
Using a procedure analogous to that described in Example 1 10 Step 1, 2-(7- bromo-r-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-l,4'-piperidine]-3-yl)acetic acid, isomer 2 was converted into 7-bromo-N-(2-adamantyl)-3-(2-(rnethyl(2- (methylamino)ethyl)amino)-2-oxoethyl)-2,3-dihydrospiro[indene-l34'-piρeridine]-r- carboxamide, isomer 2. LC-MS Method 5 tR = 1.138 min, m/z = 571.1 ; 1 H NMR (CDCl3) δ = 1.41 (m, 2H), 1.65 (m, 2H)5 1.71-1.79 (m, 8H), 1.92 (m, 2H)5 2.19 (m5 6H), 2.33-2.68 (m, 2H)5 2.79 (m, 4H), 3.01 (m, 5H), 3.32 (m, IH), 3.41 (m, IH), 3.71 (m, 2H)5 3.99 (m, 2H), 4.11-4.23 (m, IH)5 7.11 (m, 2H)5 7.42 (m, IH)5 9.51-9.72 (br, IH).
Example 116 7-Bromo-N-(2-adamantyl)-3-(2-((2-(dimethylamino)ethyl)(methyl)amino)-2-oxoethyl)-
2.3-dihydrospiro[indene- 1 ,4'-piperidine]- 1 '-carboxamide
The title compound was prepared following the procedure of Examplel 10 Step 1 using N5N5N" -trim ethylethylenediamine in place of 1 -Boc-piperazine. LC-MS Method 1 tR - 1.55 min, m/z = 585 (M+l); 1H NMR (CD3OD) δ = 7.37 (d, IH)5 7.23 (d, IH)5 7.09
(t, IH), 4.07 (d, 2H), 3.87 (s, IH), 3.85-3.74 (m5 2H)5 3.65-3.62 (m5 IH)5 3.35 (t,, 2H)5 3.1 1 (s, 3H), 2.99 (s, 3H), 2.78 (dd, IH), 2.59 (dd, IH), 2.44 (dt IH), 1.42-1.38 (m3 2H).
Example 117 7-Bromo-N-(2-adamantyl)-3-(2-(3-(dimethylamino)propylamino)-2-oxoethyl)-253- dihydrospiro[indene-l54'-piperidine]-l '-carboxamide
The title compound was prepared following the procedure of Examplel 10 Step 1 using N,N-dimethylpropylenediamine in place of 1 -Boc-piperazine. LC-MS Method 1 tR = 1.51 min5 m/z = 585 (M+); 1H NMR (CD3OD) δ = 7.37 (d, IH), 7.19 (d, IH), 7.09 (t, IH)5 4.07 (t, 2H), 3.87 (s, IH), 3.60 (m, IH)5 3.16 (dd, 2H)/288 (s, 6H), 2.76 (dd5 IH), 2.61 (dd, IH)5 2.49 (dt, IH), 2.3 (dd, IH), 1.39 (d, 2H).
Example 118 7-Bromo-N-(2-adamantyl)-3-(2-(4-(dimethylamino)butylamino)-2-oxoethyl)-2J3- dihydrospiro[indene- 1 ,4'-piperidine]- 1 '-carboxamide
The title compound was prepared following the procedure of Examplel 10 Step 1 using N,N-dimethylbutylenediamine in place of 1 -Boc-piperazine. LC-MS Method 1 tR = 1.52 min, m/z = 599 (M+). Example 119 7-Bromo-N-(2-adamantyl)-3-(2-oxo-2-(2-(piperazin-l-yl)ethylamino)ethyl)-2,3- dihydrospiro[indene-l ,4'-piperidine]-l '-carboxamide
The title compound was prepared following the procedure of Example 110 using tert-butyl 4-(2-aminoethyl)piperazine-l-carboxylate in place of 1-Boc-piperazine. LC- MS Method 1 tR = 1.41 min, m/z = 614 (M+); 1HNMR (CD3OD) δ = 7.38 (d5 IH)5 7.22 (d5 IH), 7.10 (t5 IH), 4.07 (m, 2H)5 3.87 (m, IH)3 2.90 (dd5 IH), 2.66 (dd, IH)5 2.48 Gm, IH)5 2.42 (dd, IH).
Example 120 7-Bromo-N-(2-adamantyl)-3-(2-(2-morpholinoethylammo)-2-oxoethyl)-2:,3- dihydrospiro[indene-l54'-piperidine]-r-carboxamide
The title compound was prepared following the procedure of Example 110 Step 1 using 2-morpholinoethanamine in place of 1 -Boc-piperazine. LC-MS Method 1 tR = 1.52 min, m/z = 613 (M+); IHNMR (CD3OD) δ = 7.38, 7.20, 7.10, 4.07, 2.83, 2.65, 2.48, 2.38, 1.63, 1.39.
Example 121
7-Bromo-N-(2-adamantyl)-3-(2-(2-(4-methylpiperazin-l-yl)ethylamino)-2-oxoethyl)- 2,3-dihydrospiro[indene- 154'-piperidine]-l '-carboxamide
The title compound was prepared following the procedure of Examplel 10 Step 1 using 2-(4-methylpiperazin-l -yl)ethanarnine in place of 1 -Boc-piperazine. LC-MS Method 1 tR = 1.45 min, m/z = 626 (M+); 1H NMR (CD3OD) δ = 7.38 (d, IH), 7.21 (d, IH), 7.10 (t, IH), 4.-07 (m, 3H), 3.87 (s, IH), 3.62 (m, 2H), 2.88 (s, 3H)5 2.77 (dd, 2H), 2.70 (t, 2H), 2.62 (dd, 2H), 2.49 (m, 2H), 2.34 (dd, 2H), 1.63 (d, 2H)S 1.40 (d, 2H). Example 122
(±)-7-Bromo-N-(2-adamantyl)-3-(2-hydroxyethyl)-2,3-dihydrospiro[indene-l,4'- piperidine]- 1 '-carboxamide
LiAlH4
Figure imgf000154_0002
Figure imgf000154_0001
To a solution of (±)-ethyl 2-(7-bromo-l'-((2-adaman1yl)carbamoyl)-253- dihydrospiro[indene-l54'-piperidine]-3-yl)acetate (300 mg, 0.566 mmol) in THF (5 mL) was added LiAlH4 (65 mg, 1.132 mmol) at 00C under N2. The mixture was stirred overnight at rt. The mixture was separated by preparative TLC to give the crude product, which was purified by preparative HPLC to afford (±)-7-bromo-N-(2-adamantyl)-3-(2- hydroxyethyl)-2,3-dihydrospiro[indene-l,4'-piperidine]-r-carboxamide (26 mg, 10 %). LC-MS Method 5 tR = 1.467 min, m/z = 489.1; 1H NMR: (400MHz, CDCl3): δ=1.38 (m, 2H)5 1.62 (m. 5H), 1.71 (m, 5H)5 1.75-1.88 (m, 9H), 2.19 (m, 2H)5 2.21-2.49 (m, 5H)5 2.52 (m, IH), 2.95-3.12 (m5 3H)5 3.21 (m, IH)5 3.78 (m5 2H), 3.82 (m5 3H)5 7.03 (m, IH)5 7.08 (m5 IH), 7.32 (m, IH).
Example 123
(±)-7-Bromo-N-(2-adamantyl)-3-(l-hydroxy-2-methylpropan-2-yl)-2,3- dihydrospiro[indene-l 54'-piperidine]-r-carboxamide
DIBAL
Figure imgf000154_0003
Figure imgf000154_0004
To a solution of (-t)-ethyl 2-(7-bromo-r-((2-adamantyl)carbamoyl)-2,3- dihydrospiro[indene-l,4'-piperidiπe]-3-yl)-2-methylpropanoate (18 mg, 0.0323 mmol) in dry CH2Cl2 was added DIBAL (0.15 mL, 3 eq) at -78°C. The mixture was stirred for 30 min and quenched with methanol. The organic layer was separated, dried and concentrated to give (±)-7-bromo-N-(2-adamantyl)-3-(l-hydroxy-2-methylproρan-2-yl)- 2,3-dihydrospiro[indene-l,4'-piperidine]-r-carboxamide. LC-MS Method 5 tR = 1.574 min5 m/z = 517.1; 1HNMR: (400 MHz, CDCl3): δ= 0.89 (s5 3H), 0.98 (s, 3H)5 1.22 (m, 2H)5 1.40 (m5 2H), .1.54 (m, 7H), 1.77 (m. 1 IH), 1.89 (m, 2H), 2.34 (m, 2H), 3.02 (m, 3H), 3.31 (m, IH), 3.52 (m, 2H), 3.90 (m, 3H)5 6.96 (m, IH) 7.28 (m, 2H).
Example 124
(±)-2-Adamantyl 3-(aminomethyl)-7-bromo-2,3-dihydrospiro[indene-l54'-piperidine]-r- carboxylate
Figure imgf000155_0001
A 100-mL of flask was charged with (±)-2-(7-bromo-l'-((2- adamantyloxy)carbonyl)-2,3-dihydrospiro[indene- 1 ,4'-piperidine]-3-yl)acetic acid (30 mg, 0.06 mmol) dissolved in THF (3 mL) and treated with TEA (2 ml). Then diphenylphosphoryl azide (18 mg, 0.066 mmol) was added dropwise slowly. The mixture was stirred for 3 h at rt. 1 N aq NaOH solution (3 mL) was added and the reaction mixture was reflux overnight. The solvent was removed in vacuo and the aqueous residue was extracted with CH2Cl2 (3 x 5 mL). The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC to give (±)-2-adamantyl 3-(aminomethyl)-7- bromo-2t3-dihydrospiro[indene-l,4'-piperidine]-r-carboxylate (1 mg, 4%). LC-MS Method 5 tR = 1.175 min, m/z = 475; 1H NMR (400MHz, MeOD): δ= 0.71-0.83 (m, 3H), 1.46-1.57 (m. 2H), 1.61-1.81 (m. 6H), 1.81 -2.06 (m, HH)5 2.39-2.51 (m, IH), 2.83-3.00 (m, 2H), 3.41-3.57 (m, 2H), 4.07-4.14 (m, IH), 4.79 (m, IH), 6.99-7.10 (m, 2H), 7.37 (m, IH)5 7.95-8.30 (s, IH).
Example 125 (±)-2-Adamantyl 7-bromo-3-((dimethylamino)methyl)-2,3-dihydrospiro[indene-l,4'- piperidine]-r-carboxylate
Figure imgf000155_0002
A 50-mL flask was charged with (±)-2-adamantyl 3-(aminomethyl)-7-bromo-2,3- dihydrospiro[indene-l,4'-piperidine]-r-carboxylate (60 mg, 0.12 mmol), GHaO (16 mg. 0.53 mmol) and HCOOH (33 mg, 0.72 mmol). The mixture was stirred overnight under, reflux. 6 N aq HCl (3 mL) was added and the mixture was extracted with CH2CI2 (3 x 5 mL). The aqueous layer was basifϊed with 1 N aq NaOH (10 mL) and extracted with CH2Cl2 (3 x 5 mL) The organic layers were combined, washed with brine, dried over Na2SO4, filtered and concentrated. The crude residue was purified by preparative HPLC to give (±)-2-adamantyl 7-bromo-3-((dimethylamino)methyl)-2,3-dihydrospiro[indene- l,4'-ρiperidine]-l'-carboxylate (10 mg, 9%). LC-MS Method 5 tR = 1.229 min, m/z = 503.1; 1H NMR (400MHz, MeOD): 6=1.44 (m5 2H)5 1.66 (d, 2H)5 1.72-1.90 (m, 8H), 1.94 (m, 2H), 1.98-2.10 (m, 4H), 2.38-2.50 (br, IH), 2.79 (m, IH), 3.01 (m, 6H), 3.11 (m, 2H), 3.71 (m, 2H), 4.15-4.30 (m, 2H), 7.07 (m, IH), 7.29 (d, IH)3 7.45 (d, IH).
Example 126 (±)-7-Bromo-N-(2-adamantyl)-3-(2-morpholinoethyl)-2,3-dihydrospiro[indene-l,4'- piperidine]-l '-carboxamide
Figure imgf000156_0001
Step 1 To a solution of (±)-7-bromo-N-(2-adamantyl)-3-(2-hydroxyethyl)-2,3- dihydrospiro[indene-l,4'-piperidme]-l '-carboxamide (40 mg, 0.082 mmol) and Et3N (9.9 mg, 0.098 mmol) in dry CH2Cl2 (5 mL) was added TsCl (15.6 mg, 0.082 mmol) at 00C.
The mixture was stirred overnight at rt. The mixture was concentrated to give the crude product, which was purified by preparative TLC to give (±)-7-bromo-N-(2-adamantyl)-3- (2-(p-toluenesulfonyloxy)ethyl)-2,3-dihydrospiro[indene-l,4'-piperidine]-r-carboxamide
(50 mg, crude).
Step 2
To a solution of (±)-7-bromo-N-(2-adamantyl)-3-(2-(p- toluenesuIfonyloxy)ethyl)-2,3-dihydrospiro[indene-l ,4'-piperidine]-l '-carboxamide (50 mg, 0.078 mmol) and K2CO3 (21.56 mg, 0.156mmol) in anhydrous CH3CN (3 mL) was added NaI (3 mg, 0.020 mmol) at 00C. Then the mixture was stirred overnight at 80- 900C. The mixture was concentrated to give the crude product which was purified by preparative HPLC to afford (±)-7-bromo-N-(2-adamantyl)-3-(2-morpholinoethyl)-2,3- dihydrospiro[indene-l54'-piperidine]-r-carboxamide (4 mg, 9 %). LC-MS Method 5 tR = 1.09 min5 m/z = 558; 1H NMR: (400MHz, CDCl3): δ=1.43 (m, 2H), 1.56-1.69 (m. 3H), 1.75-1.85 (m, 9H), 1.94-2.05 (m, 3H)5 2.45-2.59 (m, 4H), 2.91 (m. 2H), 3.12 (m, 5H)5 3.25 (m, 2H)5 3.56 (m, 3H), 3.91-4.16 (m, 6H)5 4.20 (m, 2H), 7.12 (m, 2H)5 7.40 (m, IH).
Example 127 (±)-3-(2-Amino-2-oxoethyl)-N-(2-adamantyl)-253-dihydrospiro[indene- 1 ,4'-piperidine]-
1 '-carboxamide
Figure imgf000157_0001
To a solution of the compound 1 (200 mg, 0.47 mmol) in CH2Cl2 (5 mL), EDCI (187 mg, 0.95 mmol), HOBt (128 mg, 0.95mmol)5 DIEA (303 mg, 2.35 mmol) were added under NH3 at 00C, and then stirred overnight. The solvent was removed under reduced pressure to give crude product, which was purified by preparative TLC to afford (±)-3-(2-amino-2-oxoethyl)-N-(2-adamantyl)-2,3-dihydrospiro[indene-l,4'-piperidine]- l'-carboxamide (110 mg, 56%). 1H NMR (CDCl3): δ = 1.52-1.61 (m, 4H), 1.62-1.66 (m, 2H), 1.68-1.70 (m, 2H), 1.75-1.76 (m, 2H)5 1.78-1.80 (m5 IH), 1.82-1.85 (m, 6H), 1.90- 1.98 (m, 2H)5 2.11-2.21 (m5 IH), 2.30-2.40 (m, IH), 2.60-2.70 (m, IH), 2.80-2.88 (m, IH), 2.95-3.15 (m, 2H), 3.65-3.75 (m, 2H), 3.76-3.88 (m5 IH), 4.00 (s, 2H), 5.40-5.55 (d, 2H), 7.15-7.25 (m, 4H).
Example 128 1 -Tert-butyl 1 '-(2-adamantyl) spiro[indoline-3,4'-piperidine]-l,r-dicarboxylate The title compound was prepared from tert-butyl spiro[indoline-354'-piperidine]- 1-carboxylate following a procedure analogous to that described in Example 24 Step 2.
Example 129 1 -Tert-butyl 1 '-(2-adamantyl) 5-fluorospiro[indoline-354'-piperidine]-l,r-dicarboxylate
The title compound was prepared from tert-butyl 5-fluorospiro[indoline-3,4'- piperidine]-l-carboxylate following a procedure analogous to that described in Example 24 Step 2.
Example 130 1-Tert-butyl 1 '-(2-adamantyl) 5-methylspiro[indoline-3,4'-piperidine]-l,r-dicarboxylate
The title compound was prepared from tert-butyl 5-methy3spiro[indoline-3,4'- piperidine]- 1 -carboxylate following a procedure analogous to that described in Example 24 Step 2.
Example 131 (±)-3-(2-amino-2-oxoethyl)-7-bromo-N-(2-adamantyl)-2,3-dihydrospiro[indene-l,4'- piperidine]- 1 '-carboxamide
The title compound was prepared from (±)-2-(7-bromo-l'-((2- adamantyl)carbamoyl)-2:,3-dihydrospiro[indene-l,4'-piperidine]-3-yl)acetic acid following a procedure analogous to that described in Example 127 except that 0.5 M NH3 in dioxane was used in place OfNH3 gas.
Compounds names were generated with the assistance of ChemDraw® software version 9.0 (Cambridgesoft, Cambridge, MA, USA).
The following tables (I - VIII) indicate those compounds of the invention that can be prepared by the methods described herein.
Figure imgf000159_0001
Table I
Figure imgf000159_0002
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0002
Figure imgf000164_0001
Table II
Figure imgf000164_0003
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
Figure imgf000168_0001
Figure imgf000169_0002
Figure imgf000169_0001
Table III
Figure imgf000169_0003
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
Figure imgf000174_0002
Figure imgf000174_0001
Figure imgf000174_0003
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0002
Figure imgf000177_0001
Table V
Figure imgf000177_0003
Figure imgf000178_0001
Figure imgf000179_0002
Figure imgf000179_0001
Table VI
Figure imgf000179_0003
Figure imgf000180_0001
Figure imgf000181_0002
Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000184_0001
Table VIII
Figure imgf000184_0002
Figure imgf000185_0001
Figure imgf000186_0001
Biological Test Example 1
The inhibition of purified 1 lβ-HSDl by compounds of Formula I or I* is measured using a Scintillation Proximity Assay. All reactions are carried out at room temperature in 96 well flexible Microbeta reaction plates. First, 1 μL of a 0.1 mM solution of a compound of Formula I or I* is mixed in DMSO diluted in half-log increments (8 points) starting at 1 μM final concentration. To this dot is added 50 μL of substrate solution (50 mM HEPES5 pH 7.4, 100 mM KCl, 5 mM NaCl, 2 mM MgCl2 containing 20μM 3H cortisone, 1 mM NADPH). After a 10 minute incubation, 50 μL of enzyme solution containing 20 nM recombinant 1 lβ-HSDl (expressed in E.coli, and affinity purified) is added. The reaction is then incubated for 90 minutes, and stopped bj' adding 50 μl of SPA bead mix (18-β-glycyrrhetinic acid, 10 μM final, 5 mg/ml protein A coated YSi SPA beads, and lug/ml α-cortisol antibody (East Coast Biologies)). The plate is shaken for 120 minutes, and the radioactivity corresponding to 3H Cortisol is measured on a Wallac Microbeta.
Biological Test Example 2
The inhibition of a microsomal preparation of 1 lβ-HSDl by compounds of the invention is measured essentially as previously described (K. Solly, et al., High- Throughput Screening of 11-Beta-Hydroxysteroid Dehydrogenase Type 1 in Scintillation Proximity Assay Format, Assay Drug Dev Technol 3 (2005) 377-384). AU reactions are carried out at room temperature in 96 well clear flexible PET Microbeta plates (PerkinElmer). First, 49 μl of substrate solution (50 mM HEPES, pH 7.4, 100 mM KCl, 5 mM NaCl5 2 mM MgCl2, 2 mM NADPH and 160 nM [3H]cortisone (1 Ci/mmol)) is mixed in 1 μL of a test compound in DMSO diluted in half-log increments (8 points) starting at 0.1 mM. After a 10 minute pre-incubation, 50 μL of enzyme solution containing microsomes isolated from CHO cells overexpressing human 1 lβ-HSDl (10- 20 μg/ml of total protein) is added, and the plates are then incubated for 90 minutes at room temperature. The reaction is stopped by adding 50 μl of the SPA beads suspension containinglO μM 18β-glycyrrhetinic acid, 5 mg/ml protein A coated YSi SPA beads (GE Healthcare) and 3.3 μg/ml of anti-cortisol antibody (East Coast Biologies) in Superblock buffer (Bio-Rad). The plates are then shaken for 120 minutes at room temperature, and the SPA signal corresponding to [3H]cortisol is measured on a Microbeta plate reader.
Biological Test Example 3
The inhibition of 1 lβ-HSDl by compounds of this invention is measured in whole cells as follows. Cells for the assay can be obtained from two sources: fully differentiated human omental adipocytes from Zen-Bio, Inc.; and human omental pre- adipocytes from Lonza Group Ltd. Pre-differentiated omental adipocytes from Zen-Bio Inc. are purchased in 96- well plates and used in the assay at least two weeks after differentiation from precursor preadipocytes. Zen-Bio induced differentiation of pre- adipocytes by supplementing medium with adipogenic and lipogemc hormones (human insulin, dexamethasone, isobutylmethylxanthine and PPAR-γ agonist). The cells are maintained in foil adipocyte medium (DMEM/Ham's F-12 (1:1, v/v), HEPES pH 7.4, fetal bovine serum, penicillin, streptomycin and Amphotericin B, supplied by Zen-Bio, Inc.) at 370C, 5% CO2.
Pre-adipocytes (purchased from Lonza Group Ltd.) are placed in culture in Preadipocyte Growth Medium-2 supplemented with fetal bovine serum, penicillin, and streptomycin (supplied by Lonza) at -370C, 5% CO2. Pre-adipocytes are differentiated by the addition of insulin, dexamethasone, indomethacin and isobutyl-methylxanthine (supplied by Lonza) to the Preadipocyte Growth Medium-2. Cells are then exposed to the differentiating factors for 7 days, at which point the cells are differentiated and ready for the assay. One day before running the assay, the differentiated omental adipocytes are transferred into serum- and phenol-red-free medium for overnight incubation. The assay is performed in a total volume of 200 μL. The cells are pre-incubated with serum- free, phenol-red-free medium containing 0.1% (v/v) of DMSO and various concentrations of the test compounds at least 1 h before [ H] cortisone in ethanol (50Ci/mmol, ARC, Inc.) is added to achieve a final concentration of cortisone of 100 nM. The cells are then incubated for 3-4 hrs at 370C, 5% CO2. Negative controls are incubated without radioactive substrate and receive the same amount of [3H] cortisone at the end of the incubation. Formation of [3H] Cortisol is monitored by analyzing 25 μL of each supernatant in a scintillation proximity assay (SPA). (Solly, K., et al., Assay Drug Dev. Technol. 2005, 3, 377-384).
The inhibition of 1 lβ-HSDl by compounds of Formulae I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, or Ii5 in whole cells is measured as follows. Omental adipocytes cultured in 96-well plates (purchased from Zen-Bio, Inc.) are used at least two weeks after differentiation from precursor preadipocytes started in medium supplemented with adipogenic and lipogenic hormones (human insulin, dexamethasone, isobutylmethylxanthine and PPARγ agonist). The cells are maintained in full adipocyte medium (DMEM/Ham's F-12 (1 :1, v/v), HEPES pH 7.4, fetal bovine serum, penicillin, streptomycin and Amphotericin B, supplied by Zen-Bio, Inc.) at 37°C, 5% CO2 and then transferred into serum-free, phenol red free medium for overnight incubation. The assay is performed in a total volume of 200 μL. The cells are pre-incubated with serum-free, phenol red free medium containing 0.1% (v/v) of DMSO and various concentrations of compounds of Formulae I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, or Ii, for at least 1 h before [3H] cortisone in ethanol (50 Ci/mmol, ARC, Inc.) is added to achieve final concentration of cortisone of 100 nM. The cells are then incubated for 3-4 h at 37°C, 5% CO2. Negative controls are incubated without radioactive substrate and receive the same amount of [3H] cortisone at the end of the incubation. Formation of [3H] Cortisol is monitored by analyzing 25 μL of each supernatant in scintillation proximity assay (SPA). (Solly, K.; et al., Assay Drug Dev. Technol. 2005, 3, 377-384).
Biological Test
Example Biological Test
Example la Example 2 a
1 -H- nt
2 -H- nt
3 -H- -H-
4 -H- nt
5 Isomer 1 -H- nt
5 Isomer 2 -H- nt
6 Isomer 1 -f nt
6 Isomer 2 ++ nt
7 -H- nt 8 nt
9 + nt
10 + nt
11 -H- nt
12 -H- nt
13 + nt
14 -f nt
15 ++ nt
16 -H- nt
17 + nt
18 4- nt
19 -H- nt
20 -H- nt
21 -H- nt
22 -H- nt
23 -H-
24 -H- nt
25 ++ nt
26 -H- nt
27 nt , Step 1 Product nt , Step 2 Product nt
28 nt -H-
29 ++ nt
30 -H-
31 -H- ++
32 nt
33 nt
34 nt ++
35 nt
36 nt
37 nt
38 nt
39 nt
40 nt
41 nt
42 nt
43 nt ++
43 Isomer 1 nt
43 Isomer 2 nt
44 nt
45 nt
46 nt
47 nt
48 nt
49 nt
50 nt ++ 51 nt
52 nt
53 nt
54 nt ++
55 nt -H-
56 nt ++
57 nt -H-
58 nt -H-
59 nt -H-
60 nt
61 nt
62 nt
63 nt
63 Isomer 1 nt
63 Isomer 2 nt
64 nt -H-
65 nt -H-
66 nt -H-
61 nt ++
68 nt -H-
69 nt -H-
70 nt -H-
71 nt -H-
72 nt +
73 nt
74 nt
74 Isomer 1 nt
74 Isomer 2 nt
74 Isomer 3 nt
75 Isomer 1 nt
75 Isomer 2 nt ++
75 Isomer 3 nt +
76 nt +
77 nt
78 nt
79 nt
80 nt +
81 nt -H-
82 nt +
83 nt
84 -H-
85 nt
86 nt ++, Step 1 Product nt
87 nt ++, Step 1 Product nt ++
88 nt 88, Step 1 Product nt nt
89 nt +
90 nt +4
91 nt ++
92 nt ++
93 nt ++
94 nt ++
95 + ++
96 nt ++
97 nt ++
98 nt +
99 nt +
100 nt -H- 101 Isomer 1 nt ++ 101 Isomer 2 nt -H-
102 nt ++
103 nt ++
103, Step 1 Product nt ++
104 nt ++
104, Step 1 Product nt nt
105 nt -H-
105, Step 1 Product nt nt
106 nt ++
107 nt ++
108 nt ++
109 nt ++ HO nt -H- H l nt -H-
112 nt -H-
1 13 nt ++
1 14 nt ++
115 nt ++ 115 Isomer 1 nt -H- 115 Isomer 2 nt -H-
116 nt ++
117 nt ++
118 nt ++
119 nt -H-
120 nt -H-
121 nt ++
122 nt ++
123 nt ++
124 nt ++
125 nt
126 nt
127 nt
128 + nt 129 + nt
130 + nt 131 nt ++ a ++ means IC50 < 50 nM, + means IC50 = 50 nM to 1000 nM; nt = not tested.
All publications, patents and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually designated as having been incorporated by reference. It is understood that the examples and embodiments described herein are for illustrative purposes only, and it will be appreciated that the invention is susceptible to modification, variation and change without departing from the proper scope or fair meaning of the appended claims.

Claims

What is claimed is:
1. A compound of Formula I* :
Figure imgf000193_0001
wherein:
K, L, M, X and Y are independently C, N or O3 provided that the total number of nitrogen and oxygen atoms in the ring is 3 or less and when K, L5 M3 X or Y is O5 any adjacent member atom in the ring cannot be O;
the bonds between K, L5 M5 X and Y are single or double bonds provided that no consecutive double bonds occur between member atoms of the ring;
n= 05 I5 or 2; s = l or 2; t = 1 or 2;
R1 - R5 are independently hydrogen, A-(5-tetrazolyl), A-(cycloalkyl), A-(heteroaryl), A-(heterocyclyl), A-(aryl), A-COOR6, A-CON(R6)2, A-COR6, A-SO2R6, A-CONHSO2R6, A-CONHSO2OR6, A-CONHSO2N(R6)25 -A-CsN5 alkyl, alkenyl, cycloalkyl, heteroaryl, heterocyclyl, aryl, or arylalkyl, wherein the alkyl, alkenyl, cycloalkyl, heteroaryl, heterocyclyl, aryl, A-(cycloalkyl), A-(heteroaryl), A-(heterocyclyl), A-(aryl) or arylalkyl groups represented by R1 - R5 are optionally and independently substituted with 1-3 groups independently selected from the group • consisting of halogen, hydroxy, cyano, -N(R6)2, -NR6C(O)N(R6)2s -NR6C(O)R6, (C,- C6)alkyl, halo(d-C6)alkyl, (Ci-C6)alkoxy, halo (C1-C6)OIkOXy5 CONH2, -SO2R6, -NR6SO2R6, -NR6SO2N(R6)2 and -NR6SO2OR6;
when K, L5 M, X5 or Y is (-O-) or (-N=), then pi, p2, p3, p4 or p5, respectively, is O; when K, L, M, X, or Y is (-N-), (-C=), or (-CH-), then pi, p2, p3, p4 or p5, respectively, is 1 ; when K, L, M, X or Y is (-C-), then pi, p2, p3, p4 or p5, respectively, is 2; and when K, L, M, X5 or Y is (-C-), and R1, R2, R3 5 R4 or R5 is connected through a double bond to K5 L5 M, X or Y5 respectively, then pi, p2, p3, p4 or p5, respectively, is 1;
A is a single bond, (Ci-C6)alkylene, (CrC6)alkenylene, (Ci-Cs)alkyleneCH=, C(O)(C0- C3)alkylene(C3-C6)cycloalkyl(Co-C3)alkylene, C(O)(C, -C6)alkylene, C(O)(C2- C6)alkenylene, S(O)2(C,-C6)alkylene, S(O)2(C2-C6)alkenylene, or S(O)2(C0- C3)alkylene(C3-C6)cycloalkyl(Co-C3)alkylene, each optionally substituted with up to 4 groups, R6;
R1, K, L and R2 are taken together to form a fused benzene or pyridine ring, which is optionally substituted with 1 -3 groups independently selected from the group consisting of halogen, hydroxy, cyano. -N(R6)2, -NR6C(O)N(R6)2, -NR6C(O)R6, (C,-C6)alkyl, halo(C,-C6)alkyL (C,-C6)alkoxy, halo(CI-C6)alkoxy, CON(R6)2, SO2N(R6)2, -SO2R6, -NR6SO2R6, -NR6SO2N(R6)2 and -NR6SO2OR6; or
R2, L, M and R3 are taken together to form a fused benzene or pyridine ring, which is optionally substituted with 1-3 groups independently selected from the group consisting of halogen, hydroxy, cyano, -N(R6)2, -NR6C(O)N(R6)2, -NR6C(O)R6, (C,-C6)alkyl, halo(C,-C6)alkyl, (C,-C6)alkoxy, halo(C,-C6)alkoxy, CON(R6)2, SO2N(R6)2, -SO2R6, -NR6SO2R6, -NR6SO2N(R6)2 and -NR6SO2OR6; or
R2, L, X and R4 are taken together, when n = O, to form a fused benzene or pyridine ring, which is optionally substituted with 1-3 groups independently selected from the group consisting of halogen, hydroxy, cyano, -N(R6)2, -NR6C(O)N(R6)2, -NR6C(O)R6, (C,- C6)alkyl, halo(CrC6)alkyl, (C,-C6)alkoxy, halo(C,-C6)alkoxy, CON(R6)2, SO2N(R6)2, -SO2R6, -NR6SO2R6, -NR6SO2N(R6)2 and -NR6SO2OR6, provided that n = 0 and M and R3 are absent; or
R4, X, Y and R5 are taken together to form a fused benzene or pyridine ring, which is optionally substituted with 1-3 groups independently selected from the group consisting of halogen, hydroxy, cyano, -N(R6)2, -NR6C(O)N(R6)2, -NR6C(O)R6, (C,-C6)alkyl5 halo(C,-C6)alkyl, (d-C6)alkoxy, halo(C1-C6)alkoxy, CON(R6)2, SO2N(R6)2, -SO2R6, -NR6SO2R6, -NR6SO2N(R6)2 and -NR6SO2OR6; or
the group consisting of R1, K, L and R2 and the group consisting of R4, X, Y and R5 are each taken together to form a fused benzene or pyridine ring, each of which is optionally substituted with 1-3 groups independently selected from the group consisting of halogen, hydroxy, cyano, -N(R6)2, -NR6C(O)N(R6)2, -NR6C(O)R6, (CrC6)alkyl, halo(C,-C6)alkyls (C,-C6)alkoxy, halo(C,-C6)alkoxy, CON(R6)2, SO2N(R6)2, -SO2R6, -NR6SO2R6, -NR6SO2N(R6)2 and -NR6SO2OR6;
R6 is hydrogen, (Ci-CI0)alkyl, halo(Ci-Ci0)alkyl, hydroxy (Ci -C, 0)alkyl, (R^2N(C1- Cio)alkyl, aryl or arylalkyl, wherein the aryl and arylalkyl groups are optionally substituted with up to three groups independently selected from halogen, hydroxy, cyano, -N(R6)2, -NR6C(O)N(R6)2, -NR6C(O)R6, (d-Q^lkyl, halo(C1-C6)alkyl, (C,- C6)alkoxy, halo(C,-C6)alkoxy, CON(R6)2, SO2N(R6)2, -SO2R6, -NR6SO2R6, -NR6SO2N(R6)2 and -NR6SO2OR6; or
N(R6)s is a heterocyclyl group containing at least one nitrogen atom, preferably selected from W1 - W7:
I — N I f — N > | — N O \ — N N-R6
W1 W2 W3 W4
Figure imgf000195_0001
W5 W6 W7
Q is O or NR6; and R7 is a saturated C7-C]2 bicycloalkyl or saturated C9-C12 tricycloalkyl in which 1-2 carbon atoms are optionally replaced with heteroatoms independently selected from N and O, and which is optionally substituted with 1-3 substituents independent^' selected from the group consisting of R6, heteroaryl, oxo-substituted heteroaryl, amino- substituted heteroaryl, heterocyclyl, oxo-substituted heterocyclyl, halogen, hydroxy, • • hydroxy(Ci-C6)alkyl, C(NOH)NH2, CONHR6, CH2CONHR6, CON(R6)2, CH2CON(R6)2, SO2NHR6, SO2N(R6)2, CO2R6, CH2CO2R6, SO2R6, NHCOR6, NR6COR6, NHCO2R6, NR6CO2R6, NHSO2R6, and NR6SO2R6;
or an enantiomer, diastereomer, geometrical isomer or pharmaceutically acceptable salt thereof:
• optionally with the general provisos that: (1) if R1, K, L and R2 form a fused benzene or pyridine ring, Q is NR6, R6 is H, Y is O, s = 1, t = 2, n = O, X is C, R4 is H and R5 is absent, then R7 is not a 7- to 10-membered carbocyclic group or heterocyclic group;
(2) if R1, K, L and R2 form a fused benzene ring, Q is NR6, R6 is H, n = I5 s = I5 1 = 1 or 2, and M, X and Y are all carbon, then at least one of R3, R4 or R5 must not be -CH2)n-Z, wherein n=0 to 2, and Z is hydrogen, (Ci-Cό)alkyl, 2-pyridyl, 3-pyridyl, 4-pyridyl or substituted or unsubstituted phenyl wherein if the phenyl is substituted, there are 1 or 2 substituents independently selected from the group consisting of halogen, (Ci-C6)alkyl, (C]-C6)alkoxy, carboxyl, cyano, loweralkylthio, carboxy-loweralkyl, nitro, -CF3 and hydroxy; and
(3) if R1 , K, L and R2 form a fused benzene ring, Q is NR6, R6 is H, n = O, s = 1 , t = Lor 2, X is C or O and Y is C or O, then at least one of R4 or R5 must not be -CH2)n-Z, wherein n=0 to 2, and Z is hydrogen, (Ci-C6)alkyl, 2-pyridyl5 3-pyridyl, 4-pyridyl or substituted or unsubstituted phenyl wherein if the phenyl is substituted, there are 1 or 2 substituents independently selected from the group consisting of halogen, (Ci-C6)alkyl,
Figure imgf000196_0001
carboxyl, cyano, loweralkylthio, carboxy-loweralkyl. nitro, -CF3 or hydroxy.
2. A compound of the Formula (I)
Figure imgf000197_0001
where
K, L, M5 X and Y are independently C, N or O5 provided that the total number of nitrogen and oxygen atoms in the ring is 3 or fewer and when K, L, M, X or Y is O3 any adjacent member atom in the ring cannot be O; the bonds between K, L, M, X and Y are single or double bonds provided that no consecutive double bonds occur between member atoms of the ring;
n= 0, 1, or 2; s = 1 or 2; t = 1 or 2; , R1 - R5 can independently be H5 A(5-tetrazolyl), ACOOR6, ACON(R6)2, ACOR6, ASO2R6, 'ACONHSO2R6. ACONHSO2N(R6)2: ACsN5 alkyl, cycloalkyl, heteroaryl, aryl or alkylaryl, wherein the cyclohexyl, heteroaryl, aryl or alkylaryl groups represented by R1 -R5 are optionally and independently substituted with 1-3 groups independently selected from the group consisting of halogen, cyano, (d-C6)alkyl5 halo(Ci-C6)alkyl5 CONH2 and NR6SO2R6, except that R1 - R5 is absent where the atom to which such R1 - R5 group would otherwise be connected is (i) O5 or (ii) an N that is connected by a double bond to an adjacent atom;
A can be a single bond, C(R6)2 or C(R6)2C(R6)2; R1 , K5 L and R2 can be taken together to form a fused benzene or pyridine ring, each of which can be optionally substituted with 1-3 groups independently selected from the group consisting of halogen, cyano, (Ci-C6)alkyl, halo(CrC6)alkyl, (Ci-C6)alkoxy, halo(C]-C6)alkoxy, CONH2 and NR6SO2R6; or
R2, L, M and R3 can be taken together to form a fused benzene or pyridine ring, each of which can be optionally substituted with 1-3 groups independently selected from the group consisting of halogen, cyano, (Ci-C6)alkyl, halo(Ci-C6)alkyl, (C]-C6)alkoxy, halo(Ci-C6)alkoxy, CONH2 and NR6SO2R6; or
R2, L3 X and R4 can be taken together, when n = 0, to form a fused benzene or pyridine ring, each of which can be optionally substituted with 1-3 groups independently selected from the group consisting of halogen, cyano, (Cj-C6)alkyl, ImIo(C1 -C6)alkyl, (Ci- C6)alkoxy, halo(C rC6)alkoxy, CONH2 and NR6SO2R6 provided that n = 0 and M and R3 are absent;
R6 is hydrogen, (Ci-Ci o) alkyl, aryl or alkylaryl and when multiple instances of R6 occur they are independently selected from the group consisting of hydrogen, (C1-CiO) alkyL aryl or alkylaryl;
Q is O or NR6;
R7 is a saturated C7-C]2 bicycloalkyl or saturated C9-C12 tricycloalkyl in which 1-2 carbon atoms are optionally replaced with heteroatoms independently selected from N and O, and which is optionally substituted with 1-3 substituents independently selected from the group consisting of R6, heteroaryl, oxo -substituted heteroaryl, amino- substituted heteroaryl, heterocyclyl, oxo-substituted heterocyclyl, halogen, hydroxy, hydroxymethyϊ, C(=NOH)NH2, CONHR6, CH2CONHR6, CON(R6)2, CH2CON(R6)2, SO2NHR6, SO2N(R6)2, CO2R6, CH2CO2R6, SO2R6, NHCOR6, NR6COR6. NHCO2R6, NR6CO2R6, NHSO2R6, NR6SO2R6; or enantiomers, diastereomers, geometrical isomers or pharmaceutically acceptable salts thereof;
with the general provisos that: ■5
(1) if R1, K, L and R2 form a fused benzene or pyridine ring, Q is NR6, R6 is H, Y is O, s = 1 , t = 2, n = 0, X is C, R4..is H and R5 is absent, then R7 is not a 7- to 10-membered carbocyclic group or heterocyclic group; 0 (2) if R1, K3 L and R2 form a fused benzene ring, Q is NR6, R6 is H, n = 1, s = 1, t = 1 or 2, and M, X and Y are all carbon, then at least one of R3, R4 or R5 must not be -(CH2)n-Z, wherein n=0 to 2, and Z is hydrogen, C] -Ce alkyl, 2-pyridyl, 3-pyridyl, 4-pyridyl or substituted or unsubstituted phenyl wherein if the phenyl is substituted, there are 1 or 2 substituents independently selected from the group consisting of halogen, Ci-C6 alkyl,5 Ci-C6 alkoxy, carboxyl, cyano, loweralkylthio, carboxyloweralkyl, nitro, -CF3 or hydroxy; and
(3) if R1 , K, L and R2 form a fused benzene ring, Q is NR6, R6 is H, n = 0, s = 1, t = 1 or 2, X is C or O and Y is C or O3 then at least one of R4 or R5 must not be -(CH2)n-Z30 wherein n=0 to 2, and Z is hydrogen, C1-CO alkyl, 2-pyridyl, 3-pyridyl, 4-pyridyl or substituted or unsubstituted phenyl wherein if the phenyl is substituted, there are 1 or 2 substituents independently selected from the group consisting of halogen, C1-C6 alkyl, Ci-Ce alkoxy5 carboxyl, cyano, loweralkylthio, carboxyloweralkyl, nitro, -CF3 or hydroxy. 5
3. The compound of claim 1 or 2, wherein K, L, M, X3 and Y are individually C or O; R1 — R3 are independently H or alkyl; and the bonds between K, L, M5 X, and Y are all single bonds. 0
4. The compound of any one of claims 1 to 3, wherein R1, K, L and R2 form a fused benzene ring.
5. The compound of any one of claims 1 to 4, wherein Q is O or NH.
6. The compound of any one of claims 1 to 5, wherein Q is NH and R7 is selected from the group consisting of 2-adamantyl, l-hydroxy-4-adamantyl, 1- hydroxymethyl-4-adamantyl, and 1 -carbamoyl -4-adamantyl.
7. The compound of any one of claims 1 to 5 wherein Q is O and R7 is selected from the group consisting of 2-adamantyl, l-hydroxy-4-adamantyl, 1- hydroxymethyl -4-adamantyl, and 1 -carbamoyl -4-adamantyl.
8. The compound of any one of claims 1 to 7, wherein n is O5 s is 1, and t is
2.
9. A compound selected from the group consisting of: tert-Butyl 1 t-((2-adamantyl)carbamoyl)spiro[indoline-3,4'-piperidine]-l -carboxylate; N-(2-Adamantyl)spiro[indoline-3,4'-piperidine]-r-carboxamide:
(±)-2-(l '-((2-Adamantyl)carbamoyl)-2,3-dihydrospiro[indene- 1 ,4'-piperidine]-3-yl)acetic acid;
(±)-Methyl 2-(r-((2-adamantyl)carbamoyl)-253-dihydrospiro[indene-l,4'-piperidine]-3- yl)acetate; (R)-Methyl 2-(l '-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene- 1 ,4'-piperidine]-3- yl)acetate;
(S^Methy^-Cr-^-adamanty^carbamoyO^S-dihydrospiroEindene-l^'-piperidinel-S- yl)acetate;
2-(r-((2-Adamantyl)carbamoyl)-2,3-dihydrospiro[mdene-l,4'-piρeridine]-3-yl)acetic acid, isomer B; l-Acetyl-N-(2-adamantyl)spiro[indoline-3!,4'-piperidine]-l1-carboxamide; r-((2-Adamantyl)carbamoyl)spiro[indene-l,4'-piperidine]-3-carboxylic acid;
(±)-r-((2-Adamantyl)carbamoyl)-2,3-dihydrospiro[indene-l,4'-piperidine]-3-carboxylic acid; (±)-r-((2-Adamantyl)carbamoyl)-253-dihydrospiro[mdene-l,4'-piperidine]-3-carboxylic acid;
Ethyl 1 '-((2-adamantyl)carbamoyl)spiro[indene-l ,4'-piperidine]-3-carboxylate; (±)-Ethyl r-(cyclohexylcarbamoyl)-2,3-dihydrospiro[indene-l,4'-piperidme]-3- carboxylate;
N-(2-Adamantyl)-l-(methylsulfonyl)spiro[indoline-334'-piperidiπe]-r-carboxamide;
2-adamantyl spiro[indoline-3 ,4'-piperidine]- 1 '-carboxylate; 2-adamantyl 5-fluorospiro[indoline-3,4'-piperidine]-l '-carboxylate;
2-adamantyl 5-methylspiro[indoline-354'-piperidϊne] -l'-carboxylate;
2-adamantyl 1 -acetylspiro[indoline-3,4'-piperidine]- 1 '-carboxylate;
(±)-2-adamantyl 3-(2-methoxy-2-oxoethyl)-2,3-dihydrospiro[indene-l,4'-piperidine]-r- carboxylate; (±)-2-(l '-((2-adamantyloxy)carbonyl)-2,3-dihydrospiro[indene-l ,4'-piperidine]-3- yl)acetic acid; and
(±)-2-adamantyl 3-(2-(methylamino)-2-oxoethyl)-2,3-dihydrospiro[indene-l,4'- piperidine]- l'-carboxylate; or an enantiomer, diastereomer, geometrical isomer or pharmaceutically acceptable salt thereof.
10. A compound selected from the group consisting of:
2-(r-((2-Adamantyl)carbamoyl)-2,3-dihydrospiro[indene-l,4'-piperidme]-3-yl)acetic acid;
N-(2-adamantyl)- 1 ,3 -dihydrospiro[indene-2,3 Vpiperidine] - 1 '-carboxamide; N-(2-adamantyl)-2,3-dihydrospiro[indene-l,4'-piperidine]-l '-carboxamide; tert-butyl 11-((2-adamantyl)carbamoyl)-l H-spiro[isoquinoline-4,4'-piperidine]-2(3H)- carboxylate;
N-(2-adamantyI)-253-dihydro-lH-spiro[isoquinoline-454'-piperidine]-l '-carboxamide;
2-acetyl-N-(2-adamantyl)-253-dihydro-lH-spiro[isoquinoline-4:,4'-piperidine]-r- carboxamide; etrryl 3 -( 1 '-((2-adamantyl)carbamoyl)- 1 H-spiro [isoquinoline-454'-piperidine]-2(3H)- yl)propanoate;
3-(r-((2-adamantyl)carbamoyl)-lH-spiro[isoquinoline-4:>4'-piperidine]-2(3H)- yl)propanoic acid; N-(2-adamantyl)-2-(methylsulfonyl)-2,3-dihydro-lH-spiro[isoquinoline-4s4'-piperidine]-
1 '-carboxamide;
Nr-(2-adamantyl)-N2-methyl-lH-spiro[isoquinoline-4,4'-piperidine]-r,2(3H)- dicarboxamide ; ethyl 1 '-((2-adamantyl)carbamoyl)- 1 H-spiro [isoquinoline-4,4'-piperidine] -2(3H)- carboxylate;
2-tert-butyl 1 r-(2-adamantyl) lH-spiro[isoquinoline-4,4'-piperidine]-l '.2(3H)- dicarboxylate; 2-adamantyl 2,3-dmydro-lH-spiro[isoquinoline-4,4'-piperidine]-r-carboxylate;
2-adamantyl 2-(methylsulfonyl)-2 ,3 -dihy dro- 1 H-spiro [isoquinoline-4,4'-piperidiπe] -V- carboxylate;
2-adamantyl 2-(isopropylsulfonyl)-2?3-dihydro-lH-spiro[isoquinoline-4,4'-piperidine]-
1 '-carboxylate; 2-adamantyl 2-(5-cyanopyridin-2-yl)-2,3-dihydro-lH-spiro[isoqumoline-4,4'-piperidine]-
1 '-carboxylate;
(±)-ethyl 2-(7-bromo-r-((2-adamantyl)carbamoyl)-253-dihydrospiro[indene-l ,4'- piperidine]-3-yl)acetate;
(-t)-2-(7-bromo-r-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-l,4'-piperidine]-3- yl)acetic acid;
2-(7-bromo-r-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-l,4'-piperidine]-3- yl)acetic acid, isomer 1;
2-(7-bromo-r-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-l,4'-piperidine]-3- yl)acetic acid, isomer 2; (-fc)-N-(2-adamantyl)-3-(2-(methylsulfonamido)-2-oxoethyl)-2.3-dihydrosρiro[indene- l,4'-piperidine]-r-carboxamide;
(±)-3-(cyanomethyl)-N-cyclohexyl-2,3-dihydrospiro[indene-l,4'-piperidine]-r- carboxamide;
(±)-3-((lH-tetrazol-5-yl)methyl)-N-(2-adamantyl)-253-dihydrospiro[indene-l54'- piperidine]-r-carboxamide;
(±)-ethyl 2-(r-((2-adamantyl)carbamoyl)-7-methyl-2,3-dihydrospiro[indene-l,4'- piperidine]-3-yl)acetate;
(±)-2-(r-((2-adamantyl)carbamoyl)-7-methyl-2,3-dihydrospiro[indene-l ,4'-piperidine]-
3-yl)acetic acid; (±)-ethyl 2-(r-((2-adamantyl)carbamoyl)-4-methyl-2,3-dihydrospiro[indene-l54'- piperidine] -3 -yl)acetate;
(±)-2-(r-((2-adamantyl)carbamoyl)-4-methyl-2,3-dihydτospiro[indene-lJ4'-piperidine]-
3-yl)acetic acid; (±)-ethyl 2-(l '-(^-adamantytycarbamoyl^-cMoro^S-dihydrospirofindene-l ,4'- piperidine]-3-yl)acetate; •». •
(±)-2-(r-((2-adamantyl)carbamoyl)-7-chloro-253-dihydrospiro[indene-l,4'-piperidine]-3- yl)acetic acid; (±)-ethyl 2-(r-((2-adamantyl)carbamoyl)-6-chloro-2,3-diliydrospiro[indene-l:,4'- piperidine] -3 -y l)acetate;
(±)-2-(r-((2-adamantyl)carbamoyl)-6-chloro-2,3-dihydrospiro[indene-l,4'-piperidine]-3- yl)acetic acid; _■ '
(±)-ethyl 2-(r-((2-adamantyl)carbamoyl)-5-chloro-2,3-dihydrospiro[indene-l,4'- piperidine]-3-yl)acetate;
(±)-2-(r-((2-adamantyl)carbamoyl)-5-chloro-2,3-dihydrospiro[indene-l,4I-piperidine]-3- yl)acetic acid;
(±)-2-(l'-((2-adaman1yl)carbainoy3)-6-rnethyl-233-dihydrospiro[indene-L4'-piperidine]-
3-yl)acetic acid; (±)-2-(l l-((2-adamantyl)carbamoyl)-5-methyl-2,3-dihydrospiro[indene-l ,4'-piperidine]-
3-yl)acetic acid;
(±)-2-(r-((2-adamantyl)carbamoyl)-6-methoxy-2,3-dihydrospiro[indene-l!,4'-piperidine]-
3-yl)acetic acid;
(±)-2-(r-((2-adamantyl)carbamoyl)-6-fluoro-2,3-dihydrospiro[indene-l,4l-piperidine]-3- yl)acetic acid;
(±^-ethy^-fV-bromo-r-CCl-adamanty^carbamoy^^jS-dihydrospiroπndene-l^'- piperidine] -3 -yl)acetate;
(±)-2-(7-bromo-l'-((l-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-ls4'-piperidine]-3- yl)acetic acid; (±)-2-(7-bromo- 1 '-((2-adamantyloxy)carbonyl)-2,3-dihydrospiro[indene-l ,4'-piperidine]-
3-yl)acetic acid; 2-(7-bromo- 1 '-((2-adamantyloxy)carbonyl)-2}3 -dihydrospirofindene- 1 ^'-piperidine] -3 - yl)acetic acid, isomer 1;
2-(7-bromo- 1 '-((2-adamantyloxy)carbonyl)-2,3 -dihydrospiro[indene- 1 ,4'-piperidine] -3 - yl)acetic acid, isomer 2;
(±)-2-(6-methyl - 1 '-((2-adamantyloxy)carbonyl)-2!>3 -dihydrospiropndene- 1 ,4'- piperidine]-3-yl)acetic acid; (±)-2-(5-methyl-r-((2-adamantyloxy)carbonyl)-2,3-dihιydrospiro[indene-l,41- piperidine]-3-yl)acetic acid;
2-(7-bromo-r-((2-adamantyl)carbamoyl)-253-dihydrόspiro[indene-l54'-piperidine3-3- yl)propanoic acid; (-fc)-ethyl 2-(7-bromo-l '-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-l ,4'- piperidine]-3-yl)-2-methylpropanoate;
(±)-2-(7-bromo-r-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-l54'-piperidine]-3- yl)-2-methylpropanoic acid;
(-t)-2-adamantyl 7-bromo-3-(2-(methylsulfonarnido)-2-oxoethyl)-2,3- dihydrospiro[indene-l54'-piperidine]-l '-carboxylate;
(±)-7-bromo-N-(2-adamantyl)-3-(2-(methylsulfonamido)-2-oxoethyI)-2,3- dihydrospiro [indene- 1.4 '-piperidine] - I'-carboxamide ;
(±)-2-adamantyl 3-(2-(dimethylamino)-2-oxoethyl)-2,3-dihydrospiro[indene- 1 ,4'- piperidine]-l '-carboxylate; 2-(l '-((1 -carbamoyl-4adamantyloxy)carbonyl)-2,3-dihydrospiro[indene-l ,4'-piperidine]-
3-yl)acetic acid;
2-(7-bromo-l '-(1 -fluoro-4-adamantylcarbamoyl)-2,3-dihydrospiro[indene-l ,4'- piperidine]-3-yl)acetic acid;
2-(7-bromo-l '-(1 -fluoro-4-adamantylcarbamoyl)-2,3-dihydrospiro[inderie-l ,4'- piperidine]-3-yl)acetic acid, isomer 1 ;
2-(7-bromo-r-(l-fiuoro-4-adamantylcarbamoyl)-2,3-dihydrospiro[indene-l,4'- piperidine]-3-yl)acetic acid, isomer 2;
2-(7-bromo-r-(l-fluoro-4-adamantylcarbamoyl)-2,3-dihydrospiro[indene-lJ4l- piperidine]-3-yl)acetic acid, isomer 3; 2-(7-bromo-r-(l-hydroxy-4-adamantylcarbamoyl)-2,3-dihydrospiro[indene-l54'- piperidine]-3-yl)acetic acid;
2-(7-bromo-r-(l-hydroxy-4-adamantylcarbamoyl)-2,3-dihydrospiro[indene-l,4'- piperidine] -3 -yl)acetic acid, isomer 1;
2-(7-bromo- 1 '-( 1 -hydroxy-4-adamantylcarbamoyl)-2,3-dihydrospiro[indene- 1 ,4'- piperidine]-3-yl)acetic acid, isomer 2;
2-(7-bromo-l'-( 1 -hydroxy-4-adamantylcarbamoyl)-2.3-dihydrosρiro[indene- 1 ,4'- piperidine]-3-yl)acetic acid, isomer 3; (±)-2-(7-bromo- 1 '-( 157-dihydroxy-4-adamantylcarbamoy l)-2,3 -dihydrospiro[indene- 1 ,4'- piperidine]-3-yl)acetic acid;
N-(2-adamantyl)-6-methoxy-3 ,4-dihydro-2H-spiro[isoquinoline-l ,4'-piperidine]- 1 '- carboxamide; N-(2-adamantyl)-354-dihydro-2H-spiro[naphthalene-l,4'-piperidine]-l '-carboxamide;
(2-adamantyl) 9-(2-methoxy-2-oxoethyl)-3-azaspiro[5.5]undecane-3-carboxylate;
2-(3-({2-adamantyl)oxycarbonyl)-3-azaspiro[5.5]undecan-9-yl)acetic acid; methyl 2-(3-((2-adamantyl)carbamoyl)-3-azaspiro[5.5]undecan-9-yl)acetate;
2-(3 -((2-adamantyl)carbamoy l)-3 -azaspiro [5.5 ] undecan-9-yl)acetic acid; N-(2-adamantyl)-3H-spiro[isobenzofuran- 1 ,4 '-piperidine]- 1 '-carboxamide;
2-adamantyl 3H-spiro[isobenzofuran-l .4'-piperidine]-r-carboxylate;
1-tert-butyl 1 '-(trans-l-carbamoyl-4-adamantyl)spiro[indoline-354'-piperidine]-l,l '- dicarboxylate;
N-(2-adamantyl)-2-methylspiro[isoindoline-l:i4'-piperdine]-r -carboxamide; N-(2-adamantyl)spiro [isoindoline- 1 ,4" -piperidine]- 1 ' -carboxamide;
7-Chloro-N-(2-adamantyl)-2-methylspiro[isoindoline- 1 ,4' -piperidine]- V -carboxamide;
2-(l '-((1 -(benzylcarbamoyl)-4-adamantyloxy)carbonyl)-2,3-dihydrospiro[indene-l ,4'- piperidine]-3-yl)acetic acid;
(±)-3-(2-amino-2-oxoethyl)-N-(2-adamantyl)-2,3-dihydrospiro[indene-l54'-ρiperidine]- 1 '-carboxamide;
1 -tert-butyl 1 '-(2-adamantyl)spiro[indolme-3,4'-piperidine3-l ,l'-dicarboxylate;
1 -tert-butyl- 1 '-(2-adamantyl) 5-fluorospiro [indoline-3 ,4'-piperidine]-l , 1 '-dicarboxylate;
1-tert-butyl-l '-(2-adamantyl) 5-meftylspiro[indoline-3,4'-piperidme]-l5l '-dicarboxylate;
(±)-3-(2-amino-2-oxoethyl)-7-bromo-N-(2-adamantyl)-2,3-dihydrospiro[indene-l54'- piperidine]- 1 '-carboxamide;
N-(2-adamantyl)-l -oxo-1.3-dihydrospiro[indene-2,3'-piperidine]-l '-carboxamide;
N-(2-adamantyl)-l-hydroxy-l53-dihydrospiro[indene-2,3'-piperi dine]-l '-carboxamide;
N-(2-adamantyl)-2-methyl-3-tbioxospiro[isoindoline-l,4'-piρeridine]-r-carboxamide;
N-(2-adamantyl)-3-tliioxospiro[isoindoline-l,4l-piperidine]-r-carboxamide; 7-chloro-N-(2-adamantyl)-2-methyl-3-thioxospiro[isoindoline-l ,4'-piperidine]-l '- carboxamide;
7-chloro-N-(2-adamantyl)-2-(4-methoxybenzyl)-3-tbioxospiro[isoindoline-l ,4'- piperidine]- l'-carboxamide; and 7-chloro-N-(2-adamantyl)-2-methyl-3-thioxospiro[isoindoline-l,4'-piperidine]-r- carboxamide; or an enantiomer, diastereomer, geometrical isomer or pharmaceutically acceptable salt thereof.
11. The compound of Claim 2, represented by the formula:
Figure imgf000206_0001
wherein:
M and X are C or N;
the bonds in the ring containing M and X are single or double bonds provided no consecutive double bonds occur between the member atoms of the ring;
n= 0, or 1; s = l ; t = 1 or 2;
R1 - R5 are independently hydrogen, COOR6, CH2COOR6, CON(R6)2j CH2CON(R6)2, COR6, SO2R6, CONHSO2R6, CH2CONHSO2R6, alkyl, cycloalkyl, heteroaryl, aryl or arylalkyl wherein the cycloalkyl, heteroaryl, aryl or arylalkyl groups represented by R1- R5 are optionally and independently substituted with 1-3 groups independently selected from the group consisting of halogen, cyano, (Ci-C6)alkyl, halo(C1-C6)alkyl5 CONH2 and NR SO2R , except that any one or more of R1 - R5 is absent where the atom to which such R1 - R5 group would otherwise be connected is (i) O, or (ii) an N that is connected by a double bond to an adjacent atom;
R6 is hydrogen, (Ci-Cio) alkyl, aryl or arylalkyl;
Q is O or NR6; and
>
R7 is a saturated C7-C12 bicycloalkyl or saturated C9-C12 tricycloalkyl in which 1-2 carbon atoms are optionally replaced with heteroatoms independently selected from N and O, and which is optionally substituted with 1-3 substituents independently selected from the group consisting of R6, heteroaryl, oxo-substituted heteroaryl, amino- substituted heteroaryl, heterocyclyl, oxo-substituted heterocyclyl, halogen, hydroxy, hydroxymethyl, C(NOH)NH2, CONHR6, CH2CONHR6, CON(R6)2, CH2CON(R6)2, SO2NHR6, SO2N(R6)2, CO2R6, CH2CO2R6, SO2R6, NHCOR6, NR6COR6, NHCO2R6, NR6CO2R6, NHSO2R6, and NR6SO2R6;
or an enantiomer, diastereomer, geometrical isomer or pharmaceutically acceptable salt thereof.
12. The compound of Claim 1, represented by the formula:
Figure imgf000207_0001
wherein:
M and X are C or N; the bonds in the ring containing M and X are single or double bonds provided no consecutive double bonds occur between the member atoms of the ring;
n= 0, or 1 ; s = l; .
or an enantiomer, diastereomer, geometrical isomer or pharmaceutically acceptable salt thereof.
13. The compound of Claim 2, represented by the formula:
Figure imgf000208_0001
wherein:
X and K are C, N or O;
s = l; t = 1 or 2; u = 0, 1, 2 or 3;
R8 is independently selected from halogen, cyano, (C]-Cδ)alkyl. halo(C)-C6)alkyl, (C]- C6)alkoxy, halo(C i -C6)alkoxy , CONH2 and NR6SO2R6;
R1, R4 and R5 are independently H5 COOR6, CH2COOR6, CON(R6)2, CH2CON(R6)2, COR6, SO2R6, CONHSO2R6, CH2CONHSO2R6, alkyl, cycloalkyl, heteroaryl, aryl or arylalkyl wherein the cyclohexyl, heteroaryl, aryl or arylalkyl groups represented by R1 and R4-R5 are optionally and independently substituted with 1 -3 groups independently selected from the group consisting of halogen, cyano, (d-C6)alkyl, hal6(Cj-C6)alkyl, CONH2 and NR6SO2R6, except that R4 or R5 is absent where the atom to which such R4 or R5 group would otherwise be connected is (i) O, or (ii) an N that is connected by a double bond to an adjacent atom;
R6 is hydrogen, (Ci-C4)alkyl, aryl or arylalkyl;
Q is O or NR6; and
R7 is a saturated C7-C]2 bicycloalkyl or saturated C9-C12 tricycloalkyl in which 1-2 carbon atoms are optionally replaced with heteroatoms independently selected from N and O, and which is optionally substituted with 1 -3 substituents independently selected from the group consisting of R6, heteroaryl, oxo-substituted heteroaryl, amino- substituted heteroaryl, heterocyclyl, oxo-substituted heterocyclyl, halogen, hydroxy, hydroxymethyl, C(NOH)NH2, CONHR6, CH2CONHR6, CON(R6)2, CH2CON(R6)2, SO2NHR6, SO2N(R6):-, CO2R6, CH2CO2R6, SO2R6, NHCOR6, NR6COR6, NHCO2R6, NR6CO2R6, NHSO2R6, and NR6SO2R6,
or an enantiomer, diastereomer, geometrical isomer or pharmaceutically acceptable salt thereof.
14. The compound of Claim 1 , represented by the formula:
Figure imgf000210_0001
wherein:
X and K are C, N or O;
s = l;
U = O9 I5 2 or 3;
R8 is independently selected from halogen, hydroxy, cyano, -N(R6)2, -NR6C(O)N(R6)2, -NR6C(O)R6, (Ci-C6)alkyl, halo(Ci-C6)alkyl, (Ci-C6)alkoxy, halo(C]-C6)alkoxy, CON(R6)2, SO2N(R6)2, -SO2R6, -NR6SO2R6, -NR6SO2N(R6)2 and -NR6SO2OR6;
or an enantiomer, diastereomer, geometrical isomer or pharmaceutically acceptable salt thereof.
15. The compound of Claim 2, represented by the formula:
Figure imgf000211_0001
wherein:
M5 X and Y are independently C, N or O5 provided that at least one of them is carbon and that when M, X, or Y is O, any adjacent member atom of the ring cannot be O;
the bonds between M and X and between X and Y are single or double bonds but are not both simultaneously double bonds;
n = 05 1 or 2; s = l; t = 1 or 2; u = 05 1, 2 or 3;
R is independently selected from halogen, cyano, (C]-C6)alkyl5 halo(Cj-C6)alkyl, (Ci- C6)alkoxy, halo(C,-C6)alkoxy, CONH2 and NR6SO2R6;
R3. R4 and R5 are independently H5 COOR6, CH2COOR6. CON(R6)2, CH2CON(R6)2, COR6, SO2R6, CONHSO2R6, CH2CONHSO2R6, alkyl, cycloalkyl, heteroaryl, aryl or arylalkyl, wherein, the cyclohexyl, heteroaryl, aryl or arylalkyl groups represented by R3- R5 are optionally and independently substituted with 1 -3 groups independently selected from the group consisting of halogen, cyano, (Ci-C6)alkyl, halo(Ci-C6)alkyl, CONH2 and NR6SO2R6, except that R4 or R3 is absent where the atom to which such R4 or R5 group would otherwise be connected is (i) O3 or (ii) an N that is connected by a double bond to an adjacent atom;
R6 is hydrogen, (Ci-C4)alkyl, aryl or arylalkyl; -v.
Q is O or NR6; and
R7 is a saturated C7-C12 bicycloalkyl or saturated C9-C12 tricycloalkyl in which 1-2 carbon atoms are optionally replaced with heteroatoms independently selected from N and O, and which is optionally substituted with 1-3 substituents independently selected from the group consisting of R6, heteroaryl, oxo-substituted heteroaryl, amino- substituted heteroaryl, heterocyclyl, oxo-substituted heterocyclyl, halogen, hydroxy, hydroxymethyl, C(NOH)NH2, CONHR6, CH2CONHR6, CON(R6)2, CH2CON(R6)2, SO2NHR6, SO2N(R6)2, CO2R6, CH2CO2R6, SO2R6, NHCOR6, NR6COR6, NHCO2R6, NR6CO2R6, NHSO2R6, and NR6SO2R6;
or an enantiomer, diastereomer, geometrical isomer or pharmaceutically acceptable salt thereof.
16. The compound of Claim 1, represented by the formula:
Figure imgf000212_0001
wherein:
M, X and Y are independently C5 N or O, provided that at least one of them is carbon and that when M, X, or Y is O, any adjacent member atom of the ring cannot be O; s= l;
U = O5 I5 2 or 3;
R8 is independently selected from halogen, hydroxy, cyano, -N(R6)2, -NR6C(O)N(R6)2s -NR6C(O)R6, (Ci-C6)alkyl, halo(Ci-C6)alkyl, (Ci-C6)alkoxy, halo(Ci-C6)alkoxy5 CON(R6)25 SO2N(R6)2, -SO2R6, -NR6SO2R6, -NR6SO2N(R6)2 and -NR6SO2OR6;
or an enantiomer, diastereomer, geometrical isomer or pharmaceutically acceptable salt thereof.
17. The compound of claim 15 or 16, where n is 0.
18. The compound of any one of claims 15 to 17, where X is C or N.
19. The compound of any one of claims 15 to 18, where Y is C.
20. The compound of any one of claims 15 to 19, where the bonds between M and X and X and Y are single bonds.
21. The compound of any one of claims 15 to 20, where s is 1 and t is 2.
22. The compound of any one of claims 15 to 21, where R4 is H, COOR6 or CH2COOR6.
23. The compound of any one of claims 15 to 22, where R5 is H.
24. The compound of any one of claims 15 to 23, where R6 is hydrogen or (C,-C4)alkyl.
25. The compound of any one of claims 15 to 24, where Q is O, NH or NR6; and R7 is 2-adamantyl, l-hydroxy-4-adamantyl, l-hydroxymethyl-4-adamantyl5 1- carbamoyl-4-adamantyl, 1 -(methylsulfonyl)-4-adamantyl, 1 -(amino sulfonyl)-4- adamantyl, 1 -bicyclo[2.2.2]octyl, l-carbamoyl-4-bicyclo[2.2.2]octyl, 9- bicyclo[3.3.1]nonyl or 3-carbamoyl-9-bicyclo[3.3.1]nonyl.
26. The compound of Claim 2, represented by the formula:
Figure imgf000214_0001
wherein:
K and Y are independently C, N or O;
s = l; t = l or 2; u = 0, 1, 2 or 3;
R8 is independently selected from halogen, cyano, (Ci-C6)alkyl, halo(Ci-C6)alkyl, (Ci- C6)alkoxy, halo(Ci-Cβ)aIkoxy, CONH2 and NR6SO2R6;
R1 and R5 are independently H, COOR6, CH2COOR6, CON(R6)2, CH2CON(R6)2, COR6, SO2R6, CONHSO2R6, CH2CONHSO2R6, alkyl, cycloalkyl, heteroaryl, aryl or arylalkyl, wherein the cycloalkyl, heteroaryl, aryl or arylalkyl group represented by R1 and R5 are optionally and independently substituted with 1-3 groups independently selected from the group consisting of halogen, cyano, (C)-C6)alkyl, halo(Ci-C6)alkyl, CONH2 and
NR6SO2R6, except that R1 or R5 is absent where the atom to which such R1 or R5 group would otherwise be connected is (i) O, or (ii) an N that is connected by a double bond to an adjacent atom; R6 is hydrogen, (Ci-COalkyl, aryl or arylalkyl;
Q is O or NR6; and
R7 is a saturated C7-Cj2 bicycloalkyl or saturated Cg-Ci2 tricycloalkyl in which 1-2 carbon atoms are optionally replaced with heteroatoms independently selected from N and O, and which is optionally substituted with 1 -3 substituents independently selected from the group consisting of R6, heteroaryl, oxo-substituted heteroaryl, amino- substituted heteroaryl, heterocyclyl, oxo-substituted heterocyclyl, halogen, hydroxy, hydroxymethyl, C(NOH)NH2, CONHR6, CH2CONHR6, CON(R6)2, CH2CON(R6)2, SO2NHR6, SO2N(R6)2, CO2R6, CH2CO2R6, SO2R6, NHCOR6, NR6COR6, NHCO2R6, NR6CO2R6, NHSO2R6, and NR6SO2R6;
or an enantiomer, diastereomer, geometrical isomer or pharmaceutically acceptable salt thereof.
27. The compound of Claim 1, represented by the formula:
Figure imgf000215_0001
wherein:
K and Y are independently C, N or O;
s = l; u = 0, 1, 2 or 3; R8 is independently selected from halogen, hydroxy, cyano, -N(R6)2, -NR6C(O)N(R6)2, -NR6C(O)R6, (C,-C6)alkyl5 halo(CrC6)alkyI5 (C,-C6)alkoxy, halo(Ci-C6)alkoxy3 CON(R6)2s SO2N(R*);,, -SO2R6, -NR6SO2R6, -NR6SO2N(R6)2 and -NR6SO2OR6;
or an enantiomer, diastereomer, geometrical isomer or pharmaceutically acceptable salt thereof.
28. The compound of Claim 27, represented by the formula:
Figure imgf000216_0001
wherein Q is O or NH; and
R7 is 2-adamantyl, 1 -hydroxy-4-adamantyl, l-(hydroxymethyl)-4-adamantyl, or 1- carbamoxyl-4-adamantyl ;
or an enantiomer. diastereomer, geometical isomer or pharmaceutically acceptable salt thereof.
29. The compound according to any one of claims 1 1-16, 26 or 27, wherein Q is O or NH.
30. The compound according to any one of claims 11-16, 26 or 27, wherein Q is O and R7 is selected from the group consisting of 2-adamantyl, l-hydroxy-4- adarnantyl, l-hydroxymethyl-4-adamantyl, and 1 -carbamoyl -4-adamantyl.
31. The compound according to any one of claims 11 - 16, 26 or 21, wherein Q is NH and R7 is selected from the group consisting of 2-adamantyl, l-hydroxy-4- adamantyl, l-hydroxymethyl-4-adamantyl, and l-carbamoyl-4-adamantyl.
32. The compound of Claim 16, represented by the formula:
Figure imgf000217_0001
or an enantiomer, diastereomer, geometrical isomer or pharmaceutically acceptable salt thereof.
33. A compound according to Claim 32. wherein:
R4 is hydrogen, A-(5-tetrazolyl), A-COOR6, ACON(R6)2, A-CONHSO2R6 or alkyl, wherein the alkyl is optionally and independently substituted with 1-3 groups independently selected from the group consisting of hydroxy, cyano, -N (R6)2, -NR6C(O)N(R6)2, -NR6C(O)R6, (Ci-C6)alkyl, halo(CrC6)alkyl, -CONH2, -SO2R6, -NR6SO2R6, -NR6SO2N(R6)2 and, -NR6SO2OR6;
A is a bond or (Ci-C3)alkylene;
s = l; t = 2; u = l ;
Q is NH or O; R7 is 2-adamantyl, 1 -hydroxy-4-adamantyl, l-hydroxymethyl-4-adamantyl, 1- carbamoyl-4-adamantyl. 1 -(methylsulfonyl)-4-adamantyl, 1 -(aminosulfonyl)-4- adamantyl., l-bicyclo[2.2.2]octyl, l-carbamoyl-4-bicyclo[2.2.2]octyl5 9- bicyclo[3.3.1]nonyl or 3-carbamoyl-9-bicyclo[3.3.1]nonyl; and
R8 is halogen or methyl.
34. The compound according to Claim 16, represented by the formula:
Figure imgf000218_0001
or an enantiomer, diastereomer, geometrical isomer or pharmaceutically acceptable salt thereof.
35. The compound according to Claim 34, wherein: R4 is hydrogen, A-COOR6, A-COR6 or A-SO2R6;
A is a single bond, (Ci-C6)alkylene, C(O)(Cj -C6)alkylene5 or S(O)2(CrC6)alkylene;
s = l; t = 2; u = l;
Q is NH or O;
R7 is 2-adamantyl, 1 -hydroxy-4-adamantyl, l-hydroxymethyl-4-adamantyl, 1- carbamoyl-4-adamantyl, l-(methylsulfonyl)-4-adamantyl, l-(aminosulfonyl)-4- adamantyl, l-bicyclo[2.2.2]octyl, l-carbamoyl-4-bicyclo[2.2.2]octyl, 9- bicyclo[3.3.1]nonyl or 3-carbamoyl-9-bicyclo[3.3.1]nonyl; and
R8 is halogen or methyl. (
36. The compound of Claim 16, represented by the formula:
Figure imgf000219_0001
or an enantiomer, diastereomer, geometrical isomer or pharmaceutically acceptable salt thereof.
37. The compound according to Claim 36, wherein: each R4 and R5 is independently selected from hydrogen and (Ci-C3)alkyl;
s = l; t = 2; u = l;
Q is NH or O;
R7 is 2-adamantyl5 l-hydroxy-4-adamantyl, l-hydroxymethyl-4-adamantyl, 1- carbamoyl-4-adamantyl, 1 -(methylsulfonyl)-4-adamantyl, l-(aminosulfonyl)-4- adamantyl, l-bicyclo[2.2.2]octyl, l-carbamoyl-4-bicyclo[2.2.2]octyl:( 9- bicyclo[3.3.1]nonyl or 3-carbamoyl-9-bicyclo[3.3.1]nonyl; and
R8 is halogen or methyl.
38. The compound according to Claim 16, represented by the formula:
Figure imgf000220_0001
or an enantiomer, diastereomer, geometrical isomer or pharmaceutically acceptable salt thereof.
39. The compound according to Claim 38, wherein: R5 is hydrogen or (Ci-C3)alkyl;
s = l; t = 2; u = l ;
Q is NH or O;
R7 is 2-adamantyl, l-hydroxy-4-adamantyl, 1 -hydroxymethyl-4-adamantyl, 1- carbamoyl-4-adamantyl, l-(methylsulfonyl)-4-adarnantyl, 1 -(aminosulfonyl)-4- adamantyl, l-bicyclo[2.2.2]octyl, l-carbamoyl-4-bicyclo[2.2.2]octyl5 9- bicyclo[3.3.1]nonyl or 3-carbamoyl-9-bicyclo[3.3.1]nonyl; and
R8 is halogen, methyl or methoxy.
40. The compound according to Claim 16, represented by the formula:
Figure imgf000221_0001
or an enantiomer, diastereomer, geometrical isomer or pharmaceutically acceptable salt thereof.
41. The compound of claim 40, wherein: R4 is A-COOR6, A-CON(R6)2, A-COR6, A-SO2R6, or alkyl;
A is a single bond, (Ci-C6)alkylene, (Ci-Cδ)alkenylene!, C(0)(Co-C3)alkylene(C3- C6)cycloalkyl(C0-C3)alkylene, C(O)(C, -C6)alkylene or S(O)2(C i-C6)alkylene, optionally substituted with up to 2 (Ci-C3)alkyl groups;
s = l ; t ~ 2; u = l;
Q is NH or O;
R7 is 2-adamantyl, 1 -hydroxy -4-adamantyl, 1 -hydroxymethyl-4-adamantyl, 1- carbamoyl-4-adamantyl, 1 -(methylsulfonyl)-4-adamantyl, l-(aminosulfonyl)-4- adamantyl, l-bicyclo[2.2.2]octyl, l-carbamoyl-4-bicyclo[2.2.2]octyl, 9- bicyclo[3.3.1]nonyl or 3-carbamoyl-9-bicyclo[3.3.1]nonyl; and
R is halogen or methyl.
42. A compound according to the formula:
Figure imgf000222_0001
wherein:
X1 is :
Figure imgf000222_0002
and X2 is NR10. or
X1 is CH2, and X2 is:
Figure imgf000222_0003
u = 0, 1, 2, 3 or 4;
R9 is oxo, hydroxy or thioxo;
R , 10 is H, (Ci-C6)alkyl, or substituted or unsubstituted arylalkyl; and R1 ' is independently selected from halogen, hydroxy, cyano, -N(R6)2, -NR6C(O)N(R6)2, -NR6C(O)R6, (C,-C6)alkyl, halo(C,-C6)alkyl, (Ci-C6)alkoxy, halo(C,-C6)alkoxy, CON(R6)2, SO2N(R6)2, -SO2R6, -NR6SO2R6, -NR6SO2N(R6)2 and -NR6SO2OR6; or a pharmaceutically acceptable salt thereof.
43. The compound according to Claim 42, wherein: X1 is :
Figure imgf000223_0001
and X2 is NR10.
44. The compound according to Claim 43, wherein R9 is thioxo.
45. The compound according to Claim 43 or 44, wherein R10 is H, methyl or 4-methoxybenzyl.
46. The compound according to Claim 42, wherein: X1 is CH2, and X2 is:
Figure imgf000223_0002
47. The compound according to Claim 46, wherein R9 is oxo or hydroxy.
48. The compound according to any one of Claims 42-47, wherein u is 1 and Rn is halogen.
49. The compound according to Claim 48, wherein R1 ' is chloro.
* 50. The compound according to any one of Claims 42-47, wherein u is 0.
51 . A compound selected from the group consisting of:
N-(2-adamantyl)-l-oxo-l;3-dihydrospiro[indene-2,3'-piperidine]-r-carboxamide;
N-(2-adamantyl)-l-hydroxy-l,3-dihydrospiro[indene-2,31-piperidine]-r- carboxamide; N-(2-adamantyl)-2-methyl-3-thioxospiro[isoindoline-l,4'-piperidine]-r- carboxamide;
N-(2-adamantyl)-3-thioxospiro[isoindoline-l,4'-piperidine]-lf-carboxamide;
7-chloro-N-(2-adamantyl)-2-methyl-3 -thioxospiro[isoindoline- 1 ,4'-piperidine] - 1 '- carboxamide; 7-chloro-N-(2-adamantyl)-2-(4-rnethoxybenzyl)-3-thioxospiro[isoindoline-l,4'- piperidine]-r-carboxamide; and
7-chloro-N-(2-adamantyl)-2-methyl-3-thioxospiro[isoindoline-l,4'-piperidine]-r- carboxamide; or a pharmaceutically acceptable salt thereof.
52. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 51, and a pharmaceutically acceptable carrier.
53. A method of modulating 1 lβ-HSDl comprising administering to a mammal in need thereof an effective amount of a compound according to any one of claims 1 to 51.
54. A method of inhibiting 11 β-HSDl comprising administering to a mammal in need thereof an effective amount of a compound according to any one of claims 1 to 51.
55. A method of inhibiting the conversion of cortisone to Cortisol in a cell comprising administering to a mammal in need thereof an effective amount of a compound according to any one of claims 1 to 51.
56. A method of inhibiting production of Cortisol in a cell comprising administering to a mammal in need thereof an effective amount of a compound according to any one of claims 1 to 51.
57. A method of increasing insulin sensitivity comprising administering to a mammal in need thereof an effective amount of a compound according to any one of claims 1 to 51.
58. A method of treating a disease or disorder associated "with activity or expression of 11 β-HSDl comprising administering to a mammal in need thereof an effective amount of a compound according to any one of claims 1 to 51.
59. The method of Claim 58, wherein the disease or disorder is selected from the group consisting of diabetes mellitus, obesity, symptoms of metabolic syndrome, glucose intolerance, hyperglycemia, hypertension, hyperlipidemia, insulin resistance, cardiovascular disease, dyslipidemia, atherosclerosis, lipodystrophy, osteoporosis, glaucoma, Cushing's syndrome, Addison's Disease, visceral fat obesity associated with glucocorticoid therapy, depression, anxiety, Alzheimer's disease, dementia, cognitive decline, polycystic ovarian syndrome and infertility.
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Cited By (45)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009001817A1 (en) * 2007-06-27 2008-12-31 Taisho Pharmaceutical Co., Ltd. COMPOUND HAVING 11β-HSD1 INHIBITORY ACTIVITY
WO2009021740A2 (en) 2007-08-15 2009-02-19 Sanofis-Aventis Substituted tetrahydronaphthalenes, process for the preparation thereof and the use thereof as medicaments
WO2010141424A1 (en) * 2009-06-02 2010-12-09 Vitae Pharmaceuticals, Inc. Carbamate and urea inhibitors of 11beta-hydroxysteroid dehydrogenase 1
WO2011059021A1 (en) * 2009-11-11 2011-05-19 大日本住友製薬株式会社 8-azabicyclo[3.2.1]octane-8-carboxamide derivative
WO2011107494A1 (en) 2010-03-03 2011-09-09 Sanofi Novel aromatic glycoside derivatives, medicaments containing said compounds, and the use thereof
WO2011157827A1 (en) 2010-06-18 2011-12-22 Sanofi Azolopyridin-3-one derivatives as inhibitors of lipases and phospholipases
WO2011161030A1 (en) 2010-06-21 2011-12-29 Sanofi Heterocyclic substituted methoxyphenyl derivatives having an oxo group, method for producing same, and use thereof as gpr40 receptor modulators
WO2012004269A1 (en) 2010-07-05 2012-01-12 Sanofi (2-aryloxy-acetylamino)-phenyl-propionic acid derivatives, method for producing same and use thereof as pharmaceuticals
WO2012004270A1 (en) 2010-07-05 2012-01-12 Sanofi Spirocyclically substituted 1,3-propane dioxide derivatives, methods for the production thereof and use of the same as medicament
WO2012010413A1 (en) 2010-07-05 2012-01-26 Sanofi Aryloxy-alkylene substituted hydroxyphenyl hexynoic acids, methods for the production thereof and use of the same as medicament
WO2013037390A1 (en) 2011-09-12 2013-03-21 Sanofi 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors
WO2013045413A1 (en) 2011-09-27 2013-04-04 Sanofi 6-(4-hydroxy-phenyl)-3-alkyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors
WO2013057944A1 (en) 2011-10-19 2013-04-25 興和株式会社 Novel spiroindoline compound, and medicinal agent comprising same
CN103168028A (en) * 2010-09-03 2013-06-19 大日本住友制药株式会社 Cyclic amide derivative
US8487094B2 (en) 2008-07-25 2013-07-16 Boehringer Ingelheim International Gmbh Synthesis of inhibitors of 11β-hydroxysteroid dehydrogenase type 1
US8552212B2 (en) 2009-11-05 2013-10-08 Boehringer Ingelheim International Gmbh Chiral phosphorus ligands
US8575156B2 (en) 2007-07-26 2013-11-05 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8592410B2 (en) 2008-05-01 2013-11-26 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11BETA-hydroxysteroid dehydrogenase 1
US8592409B2 (en) 2008-01-24 2013-11-26 Vitae Pharmaceuticals, Inc. Cyclic carbazate and semicarbazide inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8598160B2 (en) 2008-02-15 2013-12-03 Vitae Pharmaceuticals, Inc. Cycloalkyl lactame derivatives as inhibitors of 11-beta-hydroxysteroid dehydrogenase 1
US8637505B2 (en) 2009-02-04 2014-01-28 Boehringer Ingelheim International Gmbh Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8648192B2 (en) 2010-05-26 2014-02-11 Boehringer Ingelheim International Gmbh 2-oxo-1,2-dihydropyridin-4-ylboronic acid derivatives
US8673899B2 (en) 2008-05-01 2014-03-18 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8680281B2 (en) 2008-01-07 2014-03-25 Vitae Pharmaceuticals, Inc. Lactam inhibitors of 11-β-hydroxysteroid dehydrogenase 1
US8680093B2 (en) 2009-04-30 2014-03-25 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8748444B2 (en) 2007-12-11 2014-06-10 Vitae Pharmaceuticals, Inc. Cyclic urea inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8754076B2 (en) 2008-07-25 2014-06-17 Vitae Pharmaceuticals, Inc./Boehringer-Ingelheim Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8765744B2 (en) 2010-06-25 2014-07-01 Boehringer Ingelheim International Gmbh Azaspirohexanones
US8772295B2 (en) 2008-10-28 2014-07-08 The Board Of Trustees Of The Leland Stanford Junior University Modulators of aldehyde dehydrogenase and methods of use thereof
US8846613B2 (en) 2010-11-02 2014-09-30 Boehringer Ingelheim International Gmbh Pharmaceutical combinations for the treatment of metabolic disorders
US8846668B2 (en) 2008-07-25 2014-09-30 Vitae Pharmaceuticals, Inc. Inhibitors of 11beta-hydroxysteroid dehydrogenase 1
CN104080766A (en) * 2011-03-31 2014-10-01 韩国化学研究院 Sulphamide derivative having an adamantyl group and a pharmaceutically acceptable salt thereof
US8906942B2 (en) 2008-09-08 2014-12-09 The Board Of Trustees Of The Leland Stanford Junior University Modulators of aldhehyde dehydrogenase activity and methods of use thereof
US8927539B2 (en) 2009-06-11 2015-01-06 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1 based on the 1,3-oxazinan-2-one structure
US8933072B2 (en) 2010-06-16 2015-01-13 Vitae Pharmaceuticals, Inc. Substituted 5-,6- and 7-membered heterocycles, medicaments containing such compounds, and their use
US20150105456A1 (en) 2007-03-08 2015-04-16 The Board Of Trustees Of The Leland Stanford Junior University Mitochondrial Aldehyde Dehydrogenase-2 Modulators and Methods of Use Thereof
US9079861B2 (en) 2007-11-07 2015-07-14 Vitae Pharmaceuticals, Inc. Cyclic urea inhibitors of 11β-hydroxysteroid dehydrogenase 1
US9670162B2 (en) 2013-03-14 2017-06-06 The Board Of Trustees Of The Leland Stanford Junio Mitochondrial aldehyde dehyrogenase-2 modulators and methods of use thereof
EP3235813A1 (en) 2016-04-19 2017-10-25 Cidqo 2012, S.L. Aza-tetra-cyclo derivatives
CN110305141A (en) * 2019-07-18 2019-10-08 深圳市三启药物开发有限公司 A kind of spiral shell (3,3 '-isopropylpyrrolidine Oxoindole) class liver X receptor modifier and its preparation method and application
CN110330498A (en) * 2019-07-18 2019-10-15 麻王医药(深圳)有限公司 A kind of spiral shell (3,3 '-Phenylpyrrolidine Oxoindole) class liver X receptor modifier and its preparation method and application
US10457659B2 (en) 2011-04-29 2019-10-29 The Board Of Trustees Of The Leland Stanford Junior University Compositions and methods for increasing proliferation of adult salivary stem cells
CN114591327A (en) * 2022-03-25 2022-06-07 河南大学 Indoline piperidine urea type TRPV1 antagonistic and MOR agonistic double-target-point medicine, preparation method and application
US11485742B2 (en) 2019-10-09 2022-11-01 Novartis Ag 2-azaspiro[3.4]octane derivatives as M4 agonists
US11548865B2 (en) 2019-10-09 2023-01-10 Novartis Ag 2-azaspiro[3.4]octane derivatives as M4 agonists

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100298368A1 (en) * 2007-11-06 2010-11-25 Amira Pharmaceuticals, Inc. Antagonists of pgd2 receptors

Family Cites Families (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5091387A (en) * 1990-03-02 1992-02-25 Merck & Co., Inc. Spirocyclic oxytocin antagonists
EP0444945A3 (en) 1990-03-02 1992-05-13 Merck & Co. Inc. Use of spirocyclic compounds as oxytocin antagonists
CA2037287A1 (en) 1990-03-02 1991-09-03 Ben E. Evans Spirocyclic oxytocin antagonists
US5670509A (en) * 1993-09-27 1997-09-23 Merck & Co., Inc. Tocolytic oxytocin receptor antagonists
JPH09505310A (en) 1993-11-16 1997-05-27 メルク エンド カンパニー インコーポレーテッド Piperidine camphor sulfonyloxytocin antagonist
WO2001013917A1 (en) * 1999-08-26 2001-03-01 Bristol-Myers Squibb Company Npy antagonists: spiroisoquinolinone derivatives
ATE310004T1 (en) * 2000-12-12 2005-12-15 Neurogen Corp SPIRO(ISOBENZOFURAN-1,4'-PIPERIDINE)-3-ONE AND 3H-SPIROISOBENZOFURAN-1,4'-PIPERIDINE
WO2004056744A1 (en) 2002-12-23 2004-07-08 Janssen Pharmaceutica N.V. Adamantyl acetamides as hydroxysteroid dehydrogenase inhibitors
WO2005035534A1 (en) * 2003-10-08 2005-04-21 Ono Pharmaceutical Co., Ltd. Heterocyclic bicyclo ring and heterocyclic tricyclo ring compounds and drugs comprising the same
GB0328907D0 (en) 2003-12-12 2004-01-14 Syngenta Participations Ag Chemical compounds
CA2546147A1 (en) 2003-12-23 2005-07-14 Arena Pharmaceuticals, Inc. Novel spiroindoline or spiroisoquinoline compounds, methods of use and compositions thereof
JP2007531739A (en) * 2004-04-02 2007-11-08 エリクシアー ファーマシューティカルズ， インコーポレイテッド Sulfonamides and their use
ATE417837T1 (en) * 2004-05-24 2009-01-15 Amgen Inc INHIBITORS OF 11-BETA-HYDROXYSTEROID DEHYDROGENASE TYPE 1
EP1758582A4 (en) 2004-06-24 2008-01-09 Incyte Corp Amido compounds and their use as pharmaceuticals
RU2007109794A (en) 2004-08-19 2008-09-27 Вертекс Фармасьютикалз, Инкорпорейтед (Us) MUSCARINE RECEPTOR MODULATORS
EP1802623A1 (en) * 2004-10-12 2007-07-04 Novo Nordisk A/S 11beta-hydroxysteroid dehydrogenase type 1 active spiro compounds
CA2589439A1 (en) * 2004-11-29 2006-06-01 Ioana Drutu Modulators of muscarinic receptors
DE102005023784A1 (en) * 2005-05-19 2006-11-30 Grünenthal GmbH Substituted spiro compounds and their use for the preparation of medicaments
US7998959B2 (en) 2006-01-12 2011-08-16 Incyte Corporation Modulators of 11-β hydroxyl steroid dehydrogenase type 1, pharmaceutical compositions thereof, and methods of using the same
US20070208001A1 (en) * 2006-03-03 2007-09-06 Jincong Zhuo Modulators of 11- beta hydroxyl steroid dehydrogenase type 1, pharmaceutical compositions thereof, and methods of using the same

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None

Cited By (64)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9315484B2 (en) 2007-03-08 2016-04-19 The Board of Trustees—Leland Stanford Junior University Mitochondrial aldehyde dehydrogenase-2 modulators and methods of use thereof
US9102651B2 (en) 2007-03-08 2015-08-11 The Board of Trustees-Leland Stanford Junior University Mitochondrial aldehyde dehydrogenase-2 modulators and methods of use thereof
US20150105456A1 (en) 2007-03-08 2015-04-16 The Board Of Trustees Of The Leland Stanford Junior University Mitochondrial Aldehyde Dehydrogenase-2 Modulators and Methods of Use Thereof
WO2009001817A1 (en) * 2007-06-27 2008-12-31 Taisho Pharmaceutical Co., Ltd. COMPOUND HAVING 11β-HSD1 INHIBITORY ACTIVITY
US8222417B2 (en) 2007-06-27 2012-07-17 Taisho Pharmaceutical Co., Ltd Compound having 11β-HSD1 inhibitory activity
US8575156B2 (en) 2007-07-26 2013-11-05 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1
WO2009021740A2 (en) 2007-08-15 2009-02-19 Sanofis-Aventis Substituted tetrahydronaphthalenes, process for the preparation thereof and the use thereof as medicaments
US9079861B2 (en) 2007-11-07 2015-07-14 Vitae Pharmaceuticals, Inc. Cyclic urea inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8748444B2 (en) 2007-12-11 2014-06-10 Vitae Pharmaceuticals, Inc. Cyclic urea inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8680281B2 (en) 2008-01-07 2014-03-25 Vitae Pharmaceuticals, Inc. Lactam inhibitors of 11-β-hydroxysteroid dehydrogenase 1
US8592409B2 (en) 2008-01-24 2013-11-26 Vitae Pharmaceuticals, Inc. Cyclic carbazate and semicarbazide inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8598160B2 (en) 2008-02-15 2013-12-03 Vitae Pharmaceuticals, Inc. Cycloalkyl lactame derivatives as inhibitors of 11-beta-hydroxysteroid dehydrogenase 1
US8673899B2 (en) 2008-05-01 2014-03-18 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8592410B2 (en) 2008-05-01 2013-11-26 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11BETA-hydroxysteroid dehydrogenase 1
US8846668B2 (en) 2008-07-25 2014-09-30 Vitae Pharmaceuticals, Inc. Inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8754076B2 (en) 2008-07-25 2014-06-17 Vitae Pharmaceuticals, Inc./Boehringer-Ingelheim Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8487094B2 (en) 2008-07-25 2013-07-16 Boehringer Ingelheim International Gmbh Synthesis of inhibitors of 11β-hydroxysteroid dehydrogenase type 1
US8906942B2 (en) 2008-09-08 2014-12-09 The Board Of Trustees Of The Leland Stanford Junior University Modulators of aldhehyde dehydrogenase activity and methods of use thereof
US9345693B2 (en) 2008-09-08 2016-05-24 The Board of Trustees-Leland Stanford Junior University Modulators of aldehyde dehydrogenase activity and methods of use thereof
US8772295B2 (en) 2008-10-28 2014-07-08 The Board Of Trustees Of The Leland Stanford Junior University Modulators of aldehyde dehydrogenase and methods of use thereof
US8637505B2 (en) 2009-02-04 2014-01-28 Boehringer Ingelheim International Gmbh Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8680093B2 (en) 2009-04-30 2014-03-25 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
WO2010141424A1 (en) * 2009-06-02 2010-12-09 Vitae Pharmaceuticals, Inc. Carbamate and urea inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US9163012B2 (en) 2009-06-02 2015-10-20 Vitae Pharmaceuticals, Inc. Carbamate and urea inhibitors of 11β-hydroxysteroid dehydrogenase 1
JP2012528865A (en) * 2009-06-02 2012-11-15 ヴァイティー ファーマシューティカルズ，インコーポレイテッド Carbamate and urea inhibitors of 11β hydroxysteroid dehydrogenase 1
US8927539B2 (en) 2009-06-11 2015-01-06 Vitae Pharmaceuticals, Inc. Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1 based on the 1,3-oxazinan-2-one structure
US8552212B2 (en) 2009-11-05 2013-10-08 Boehringer Ingelheim International Gmbh Chiral phosphorus ligands
TWI472331B (en) * 2009-11-11 2015-02-11 Sumitomo Dainippon Pharma Co Ltd 8-azabicyclo[3.2.1]octane-8-carboxamide derivative
WO2011059021A1 (en) * 2009-11-11 2011-05-19 大日本住友製薬株式会社 8-azabicyclo[3.2.1]octane-8-carboxamide derivative
CN102596949B (en) * 2009-11-11 2015-08-19 大日本住友制药株式会社 8-azabicyclo [3.2.1] octane-8-carboxamide derivative
CN102596949A (en) * 2009-11-11 2012-07-18 大日本住友制药株式会社 8-azabicyclo[3.2.1]octane-8-carboxamide derivative
US8933229B2 (en) 2009-11-11 2015-01-13 Sumitomo Dainippon Pharma Co., Ltd. 8-azabicyclo[3.2.1]octane-8-carboxamide derivative
WO2011107494A1 (en) 2010-03-03 2011-09-09 Sanofi Novel aromatic glycoside derivatives, medicaments containing said compounds, and the use thereof
US8648192B2 (en) 2010-05-26 2014-02-11 Boehringer Ingelheim International Gmbh 2-oxo-1,2-dihydropyridin-4-ylboronic acid derivatives
US9090605B2 (en) 2010-06-16 2015-07-28 Vitae Pharmaceuticals, Inc. Substituted 5-,6- and 7-membered heterocycles, medicaments containing such compounds, and their use
US8933072B2 (en) 2010-06-16 2015-01-13 Vitae Pharmaceuticals, Inc. Substituted 5-,6- and 7-membered heterocycles, medicaments containing such compounds, and their use
WO2011157827A1 (en) 2010-06-18 2011-12-22 Sanofi Azolopyridin-3-one derivatives as inhibitors of lipases and phospholipases
WO2011161030A1 (en) 2010-06-21 2011-12-29 Sanofi Heterocyclic substituted methoxyphenyl derivatives having an oxo group, method for producing same, and use thereof as gpr40 receptor modulators
US8765744B2 (en) 2010-06-25 2014-07-01 Boehringer Ingelheim International Gmbh Azaspirohexanones
WO2012010413A1 (en) 2010-07-05 2012-01-26 Sanofi Aryloxy-alkylene substituted hydroxyphenyl hexynoic acids, methods for the production thereof and use of the same as medicament
WO2012004269A1 (en) 2010-07-05 2012-01-12 Sanofi (2-aryloxy-acetylamino)-phenyl-propionic acid derivatives, method for producing same and use thereof as pharmaceuticals
WO2012004270A1 (en) 2010-07-05 2012-01-12 Sanofi Spirocyclically substituted 1,3-propane dioxide derivatives, methods for the production thereof and use of the same as medicament
US8895552B2 (en) 2010-09-03 2014-11-25 Sumitomo Dainippon Pharma Co., Ltd. Cyclic amide derivative
CN103168028A (en) * 2010-09-03 2013-06-19 大日本住友制药株式会社 Cyclic amide derivative
US8846613B2 (en) 2010-11-02 2014-09-30 Boehringer Ingelheim International Gmbh Pharmaceutical combinations for the treatment of metabolic disorders
CN104080766A (en) * 2011-03-31 2014-10-01 韩国化学研究院 Sulphamide derivative having an adamantyl group and a pharmaceutically acceptable salt thereof
CN104080766B (en) * 2011-03-31 2017-02-15 韩国化学研究院 Sulphamide derivative having an adamantyl group and a pharmaceutically acceptable salt thereof
US10457659B2 (en) 2011-04-29 2019-10-29 The Board Of Trustees Of The Leland Stanford Junior University Compositions and methods for increasing proliferation of adult salivary stem cells
WO2013037390A1 (en) 2011-09-12 2013-03-21 Sanofi 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors
WO2013045413A1 (en) 2011-09-27 2013-04-04 Sanofi 6-(4-hydroxy-phenyl)-3-alkyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors
WO2013057944A1 (en) 2011-10-19 2013-04-25 興和株式会社 Novel spiroindoline compound, and medicinal agent comprising same
US8921576B2 (en) 2011-10-19 2014-12-30 Kowa Company, Ltd. Spiroindoline compound, and medicinal agent comprising same
US10227304B2 (en) 2013-03-14 2019-03-12 The Board Of Trustees Of The Leland Stanford Junior University Mitochondrial aldehyde dehydrogenase-2 modulators and methods of use thereof
US9670162B2 (en) 2013-03-14 2017-06-06 The Board Of Trustees Of The Leland Stanford Junio Mitochondrial aldehyde dehyrogenase-2 modulators and methods of use thereof
EP3235813A1 (en) 2016-04-19 2017-10-25 Cidqo 2012, S.L. Aza-tetra-cyclo derivatives
WO2017182464A1 (en) 2016-04-19 2017-10-26 Cidqo 2012, S.L. New aza- tetracyclo derivatives
CN110305141A (en) * 2019-07-18 2019-10-08 深圳市三启药物开发有限公司 A kind of spiral shell (3,3 '-isopropylpyrrolidine Oxoindole) class liver X receptor modifier and its preparation method and application
CN110330498A (en) * 2019-07-18 2019-10-15 麻王医药(深圳)有限公司 A kind of spiral shell (3,3 '-Phenylpyrrolidine Oxoindole) class liver X receptor modifier and its preparation method and application
WO2021008173A1 (en) * 2019-07-18 2021-01-21 深圳市三启药物开发有限公司 Spiro (3,3'-isopropyl pyrrolidine oxindole) liver x receptor regulator, preparation method therefor, and use thereof
CN110330498B (en) * 2019-07-18 2022-03-08 麻王医药(深圳)有限公司 Spiro (3, 3' -phenylpyrrole alkoxylated indole) liver X receptor regulator and preparation method and application thereof
US11485742B2 (en) 2019-10-09 2022-11-01 Novartis Ag 2-azaspiro[3.4]octane derivatives as M4 agonists
US11548865B2 (en) 2019-10-09 2023-01-10 Novartis Ag 2-azaspiro[3.4]octane derivatives as M4 agonists
US11820778B2 (en) 2019-10-09 2023-11-21 Novartis Ag 2-azaspiro[3.4]octane derivatives as M4 agonists
CN114591327A (en) * 2022-03-25 2022-06-07 河南大学 Indoline piperidine urea type TRPV1 antagonistic and MOR agonistic double-target-point medicine, preparation method and application

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