GAMMA SECRETASE MODULATORS

FIELD OF THE INVENTION

The present invention relates to certain heterocyclic compounds useful as gamma secretase modulators, pharmaceutical compositions containing the compounds, and methods of treatment using the compounds and compositions to treat various diseases including central nervous system disorders such as, for example, neurodegenerative diseases such as Alzheimer's disease and other diseases relating to the deposition of amyloid protein. They are especially useful for reducing Amyloid beta (hereinafter referred to as Aβ) production which is effective in the treatment of diseases caused by Aβ such as, for example, Alzheimers and Down Syndrome.

BACKGROUND OF THE INVENTION

Alzheimer's disease is a disease characterized by degeneration and loss of neurons and also by the formation of senile plaques and neurofibrillary change. Presently, treatment of Alzheimer's disease is limited to symptomatic therapies with a symptom-improving agent represented by an acetylcholinesterase inhibitor, and the basic remedy which prevents progress of the disease has not been developed. A method of controlling the cause of onset of pathologic conditions needs to be developed tor creation of the basic remedy of Alzheimer's disease.

Aβ protein, which is a metabolite of amyloid precursor protein (hereinafter referred to as APP), is considered to be greatly involved in degeneration and loss of neurons as well as onset of demential conditions (for example, see Klein W L, et al Proceeding National Academy of Science USA, Sep. 2, 2003, 100(18), p. 10417-22, suggest a molecular basis for reversible memory loss.

Nitsch R M, and 16 others, Antibodies against β-amyloid slow cognitive decline in Alzheimer's disease, Neuron, May 22, 2003, 38(4), p. 547-554) suggest that the main components of Aβ protein are Aβ40 consisting of 40 amino acids and Aβ42 having two additional amino acids at the C-terminal. The Aβ40 and Aβ42 tend to aggregate (for example, see Jarrell J T et al, The carboxy terminus of the β amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer's disease, Biochemistry, May 11, 1993, 32(18), p. 4693-4697) and constitute the main components of senile plaques (for example, (Glenner G G, et al, Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein, Biochemical and Biophysical Research Communications, May 16, 1984, 120(3), p. 885-90. See also Masters C L, et al, Amyloid plaque core protein in Alzheimer disease and Down syndrome, Proceeding National Academy of Science USA, June 1985, 82(12), p. 4245-4249.).

Furthermore, it is known that mutations of APP and presenelin genes, which are observed in familial Alzheimer's disease, increase production of Aβ40 and Aβ42 (for example, see Gouras G K, et al, Intraneuronal Aβ142 accumulation in human brain, American Journal of Pathology, January 2000, 156(1), p. 15-20. Also, see Scheuner D, et al, Nature Medicine, August 1996, 2(8), p. 864-870; and Forman M S, et al, Differential effects of the Swedish mutant amyloid precursor protein on β-amyloid accumulation and secretion in neurons and normeuronal cells, Journal of Biological Chemistry, Dec. 19, 1997, 272(51), p. 32247-32253.). Therefore, compounds which reduce production of Aβ40 and Aβ42 are expected to be agents for controlling progress of Alzheimer's disease or for preventing the disease.

These Aβs are produced when APP is cleaved by beta secretase and subsequently cleaved by gamma secretase. In consideration of this, creation of inhibitors of γ-secretase and β-secretase has been attempted for the purpose of reducing production of Aβs. Many of these known secretase inhibitors are peptides or peptidomimetics such as L-685,458. L-685,458, an aspartyl protease transition state mimic, is a potent inhibitor of γ-secretase activity, (Biochemistry; Aug. 1, 2000, 39(30), p. 8698-8704).

Also of interest in connection with the present invention are: US 2007/0117798 (Eisai, published May 24, 2007); US 2007/0117839 (Eisai, published May 24, 2007); US 2006/0004013 (Eisai, published Jan. 5, 2006); WO 2005/110422 (Boehringer Ingelheim, published Nov. 24, 2005); WO 2006/045554 (Cellzone A G, published May 4, 2006); WO 2004/110350 (Neurogenetics, published Dec. 23, 2004); WO 2004/071431 (Myriad Genetics, published Aug. 26, 2004); US 2005/0042284 (Myriad Genetics, published Feb. 23, 2005) and WO 2006/001877 (Myriad Genetics, published Jan. 5, 2006).

There is a need for new compounds, formulations, treatments and therapies to treat diseases and disorders associated with Aβ. It is, therefore, an object of this invention to provide compounds useful in the treatment or prevention or amelioration of such diseases and disorders.

SUMMARY OF THE INVENTION

In its many embodiments, the present invention provides a novel class of heterocyclic compounds as gamma secretase modulators (including inhibitors, antagonists and the like), methods of preparing such compounds, pharmaceutical compositions comprising one or more such compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention, inhibition or amelioration of one or more diseases associated with the Aβ using such compounds or pharmaceutical compositions.

One embodiment, of the present invention is directed to compounds of formula (I):

or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein R¹, R², R³, R⁴, and L are as defined below.

This invention also provides compounds of formula (I).

This invention also provides compounds of formula (I) in pure and isolated form.

This invention also provides compounds of formula (I) selected from the group consisting of: compounds of formulas IA to 35A, 35A.1, 35A2, 45A-49A, 52A to 79A, 82A to 88A, 91A to 97A, 100A and 101A.

This invention also provides compounds of formula (I) selected from the group consisting of: compounds of formulas IA.1, IA, IB.1, IB, IC, ID.1, ID, IE.1, IE, B2, B3, B5-B9, B11, B13-B35, B45 to B49, B52 to B74, B45.1 to B49.1, B52.1 to B74.1, B75 to B77, and 1 to 162 (identified below).

This invention also provides compounds of formula (I) selected from the group consisting of: compounds of formulas B2, B3, B5-B9, B11, B13-B35, B45 to B49, B52 to B74, B45.1 to B49.1, B52.1 to B74.1, B75 to B77, and 1 to 162 (identified below).

This invention also provides compounds of formula (I) selected from the group consisting of: compounds of formulas B2, B3, B5-B9, B11, and B13 to B35.

This invention also provides compounds of formula (I) selected from the group consisting of: compounds of formulas B45 to B49 and B52 to B74.1.

This invention also provides compounds of formula (I) selected from the group consisting of: compounds of formulas B45.1 to B49.1 and B52.1 to B74.1.

This invention also provides compounds of formula (I) selected from the group consisting of: compounds of formulas B75 to B77.

This invention also provides compounds of formula (I) selected from the group consisting of: compounds of formulas I to 162 (identified below).

This invention also provides pharmaceutical compositions comprising an effective amount of one or more (e.g., one) compounds of formula (I), or a pharmaceutically acceptable salt, ester or solvate thereof, and an effective amount of one or more (e.g., one) other pharmaceutically active ingredients (e.g., drugs), and a pharmaceutically acceptable carrier.

Thus, this invention also provides methods for: (1) method for modulating (including inhibiting, antagonizing and the like) gamma-secretase; (2) treating one or more neurodegenerative diseases; (3) inhibiting the deposition of amyloid protein (e.g., amyloid beta protein) in, on or around neurological tissue (e.g., the brain); (4) Alzheimer's disease: and (5) treating Downs syndrome; wherein each method comprises administering an effective amount of one or more (e.g., one) compounds of formula (I) to a patient in need of such treatment.

This invention also provides combination therapies for (1) modulating gamma-secretase, or (2) treating one or more neurodegenerative diseases, or (3) inhibiting the deposition of amyloid protein (e.g., amyloid beta protein) in, on or around neurological tissue (e.g., the brain), or (4) treating Alzheimer's disease. The combination therapies are directed to methods comprising the administration of an effective amount of one or more (e.g. one) compounds of formula (I) and the administration of an effective amount of one or more (e.g., one) other pharmaceutical active ingredients (e.g., drugs).

This invention also provides methods for (1) treating mild cognitive impairment; (2) treating glaucoma; (3) treating cerebral amyloid angiopathy; (4) treating stroke; (5) treating dementia; (6) treating microgliosis; (7) treating brain inflammation; and (8) treating olfactory function loss; wherein each method comprises administering an effective amount of one or more (e.g., one) compounds of formula (I) to a patient in need of such treatment.

This invention also provides a kit comprising, in separate containers, in a single package, pharmaceutical compositions for use in combination, wherein one container comprises an effective amount of a compound of formula (I) in a pharmaceutically acceptable carrier, and another container (i.e., a second container) comprises an effective amount of another pharmaceutically active ingredient (as described below), the combined quantities of the compound of formula (I) and the other pharmaceutically active ingredient being effective to treat the diseases or conditions mentioned in any of the above methods.

This invention also provides any of the above mentioned methods, pharmaceutical compositions or kit wherein the compound of formula (I) is selected from the group consisting of: compounds of formulas IA to 35A, 35A.1, 35A.2, 45A-79A, 82A to 88A, 91A to 97A, 100A and 101A.

This invention also provides any of the above mentioned methods, pharmaceutical compositions or kit wherein the compound of formula (I) is selected from the group consisting of: compounds IA.1, IA, IB.1, IB, IC, ID.1, ID, IE.1, IE, B2, B3, B5-B9, B11, B13-B35, B45 to B74, B45.1 to B74.1, B75 to B77, and 1 to 162 (identified below).

This invention also provides any of the above mentioned methods, pharmaceutical compositions or kit wherein the compound of formula (I) is selected from the group consisting of: compounds B2, B3, B5-B9, B11, B13-B35, B45 to B74, B45.1 to B74.1, B75 to B77, and 1 to 162 (identified below).

This invention also provides any of the above mentioned methods, pharmaceutical compositions or kit wherein the compound of formula (I) is selected from the group consisting of: compounds B45 to B74.

This invention also provides any of the above mentioned methods, pharmaceutical compositions or kit wherein the compound of formula (I) is selected from the group consisting of: compounds B75 to B77.

DETAILED DESCRIPTION OF THE INVENTION

This invention provides compounds, useful as gamma secretase modulators, of formula (I):

or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein:

R¹, R², R³, R⁴and L are each independently selected;

R¹is selected from the group consisting of: alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl (e.g., heterocycloalkyl), cycloalkenyl, aryl (e.g., phenyl), heteroaryl (e.g., pyridyl), heterocyclenyl (i.e., heterocycloalkenyl), fused cycloalkylaryl (i.e., cycloalkyfusedlaryl-), fused heterocycloalkylaryl- (i.e., heterocycioalkylfusedaryl-), fused cycloalkylheteroaryl- (i.e., cycloalkylfusedheteroary-), fused heterocycloalkylheteroaryl- (i.e., heterocycloalkylfusedheteroaryl-), fused benzocycloalkylalkyl- (i.e., benzefusedcycloalkylalkyl-), fused benzoheterocycloalkylalkyl- (i.e., benzofusedheterocycloalkylalkyl-), fused heteroarylcycloalkylalkyl- (i.e., heteroarylfusedcycloalkylalkyl-), fused heteroarylheterocycloalkylalkyl- (i.e., heteroarylfusedheterocycloalkylalkyl-), fused cycloalkylarylalkyl- (i.e., cycloalkyfusedlarylalkyl-), fused heterocycloalkylarylalkyl- (i.e., heterocycloalkylfusedarylalkyl-), fused cycloalkylheteroarylalkyl- (i.e., cycloalkylfusedheteroarylalkyl-), fused heterocycloalkyll heteroarylalkyl- (i.e., heterocycloalkylfusedheteroarylalkyl-), and wherein each of said: alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkenyl, aryl, heteroaryl, heterocyclenyl, fused cycloalkylaryl, fused heterocycloalkylaryl-, fused cycloalkylheteroaryl-, fused heterocycloalkylheteroaryl-, fused benzocycfoalkylalkyl-, fused benzoheterocycloalkylalkyl-, fused heteroarylcycloalkylalkyl-, fused heteroarylheterocycloalkylalkyl-, fused cycloalkylarylalkyl-, fused heterocycloalkylarylalkyl-, fused cycloalkylheteroarylalkyl-, and fused heterocycloalkylheteroarylalkyl- R¹groups is optionally substituted with 1-5 independently selected R²¹groups;

L is selected from the group consisting of: L is a direct bond, —O—, —N(R⁵)—, —C(R⁶)(R⁷)—, —(C═O)—, —(C═NR^21A)—, —S—, —S(O)—, and —S(O)₂—;

R²is the fused bicyclic ring:

wherein:

(1) Ring (A) is a five membered heteroaryl ring comprising atoms A¹to A⁵, or Ring (A) is a five membered heterocycloalkenyl ring comprising atoms A¹to A⁵(wherein the dashed circle in Ring A represents a sufficient number of bonds for Ring (A) to be a heteroaryl ring, or for Ring (A) to be a heterocycloalkenyi ring, thus the dashed circle represents at feast one bond), and:

- (i) when Ring (A) is a heteroaryl ring:
  - (a) A¹, A⁴, and A⁵are each independently selected from the group consistrg of C and N,
  - (b) A²and A³are each independently selected from the group consisting of: N, S, O or C, and wherein each substitutable C is optionally substituted with one R^21Bgroup and each R^21Bfor each C is independently selected, and wherein each substitutable N is optionally substituted with one R^21Agroup and each R^21Afor each N is independently selected,
  - (c) provided that at least one (e.g., 1 to 3, or 1 to 2, or 1) of A¹to A⁵is a heteroatom (i.e., at least one of A¹to A⁵is selected from the group consisting of N, S and O), and provided that the total number of heteroatoms in Ring (A) is 1 to 3, and
  - (d) provided that Ring (A) does not contain two adjacent ring O atoms, and does not contain adjacent O and S atoms (i.e., there are no —O—O—, and no —O—S—, and no —S—O— ring members in Ring (A)), and
- (ii) when ring (A) is a heterocycloalkenyl ring:
  - (a) A¹, A⁴, and A⁵are each independently selected from the group consisting of C and N, and wherein each substitutable C is optionally substituted with one R^21Bgroup and each R^21Bfor each C is independently selected, and wherein each substitutable N is optionally substituted with one R^21Agroup and each R^21Afor each N is independently selected,
  - (b) A²and A³are each independently selected from the group), and wherein each substitutable C is optionally substituted with one R^21Bgroup and each R^21Bfor each C is independently selected, and wherein each substitutable N is optionally substituted with one R^21Agroup and each R^21Afor each N is independently selected,
  - (c) provided that at least one (e.g., 1 to 3, or 1 to 2, or 1) of A¹to A⁵is a heteroatom (i.e., at least one of A¹to A⁵is selected from the group consisting of N, S, SO, SO₂and O), and provided that the total number of heteroatoms in Ring (A) is 1 to 3, and
  - (d) provided that Ring (A) does not contain two adjacent ring O atoms, and does not contain two adjacent S groups (e.g., does not contain two adjacent groups selected from the group consisting of —S—, —S(O)— and —S(O)₂), and does not contain adjacent O atom and S groups (i.e., there are no —O—O—, and no —O—S—, and no —O—SO—, and no O—SO₂—, and no —S—O— ring members in Ring (A)),

(2) Ring (B) (which comprises atoms A⁴, A⁵, and B¹to B⁴) is a cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl or phenyl ring, and

- (a) A⁴and A⁵are as defined for Ring (A) above,
- (b) in said phenyl Ring (B):
  - (i) A⁴, A⁵, and B¹to B⁴are C, and
  - (ii) B², B³, and B⁴are each optionally substituted with one R^21Bgroup (and the substitution on each carbon is independent of the substitutions on the remaining carbons),
- (c) in said cycloalkyl Ring (B):
  - (i) A⁴, A⁵, and B¹are C,
  - (ii) B², B³, and B⁴are each independently selected from the group consisting of: C, —(C═O)— and —(C═NR^21A)— (e.g., —(C═N—OR¹⁵)—, and —(C═N—N(R¹⁵)(R¹⁶))—), provided that there are only 0 to 2 moieties selected from the group consisting of —(C═O)— and —(C═NR^21A)— (i.e. in said cycloalkyl Ring (B) either B², B³, and B⁴are all C, or one of B², B³, and B⁴is C and the remaining two are selected from the group consisting of —(C═O)— and —(C═NR^21A)—, or two of B², B³, and B⁴are C and the remaining one is selected from the group consisting of: —(C═O)— and —(C═NR^21A)—), and
  - (iii) each substitutable A⁴, A⁵, and B¹to B⁴C is optionally substituted with 1 or 2 independently selected R^21Bgroups (and the substitution on each carbon is independent of the substitutions on the remaining carbons, and those skilled in the art will appreciate that the total number of optional substitutents on a carbon is determined by the number bonds in the ring to the ring atom),
- (d) in said cycloalkenyl Ring (B):
  - (i) A⁴, A⁵, and B¹are C,
  - (ii) B², B³, and B⁴are each independently selected from the group consisting of: C, —(C═O)— and —(C═NR^21A)— (e.g., —(C═N—OR¹⁵)—, and —(C═N—N(R¹⁵)(R¹⁶))—), provided that there are only 0 to 2 moieties selected from the group consisting of C═O and —C═NR^21A(i.e. in said cycloalkenyl Ring (B) either B², B³, and B⁴are all C, or one of B², B³, and B⁴is C and the remaining two are selected from the group consisting of —(C═O)— and —(C═NR^21A)—, or two of B², B³, and B⁴are C and the remaining one is selected from the group consisting of: —(C═O)— and
  - (iii) each substitutable A⁴, A⁵, and B¹to B⁴C is optionally substituted with 1 or 2 independently selected R^21Bgroups (and the substitution on each carbon is independent of the substitutions on the remaining carbons, and those skilled in the art will appreciate that the total number of optional substitutents on a carbon is determined by the number bonds in the ring to the ring atom), and

(iv) said cycloalkenyl Ring (B) comprises one or two double bonds (and in one example one double bond, and in another example two double bonds),

- (e) in said heterocycloalkyl Ring (B):
  - (i) B¹is selected from the group consisting of N and C,
  - (ii) B², B³and B⁴are each independently selected from the group consisting of: N, C, —(C═O)— and —(C═NR^21A)— e.g., —(C═N—OR¹⁵)—, and —(C═N—N(R¹⁵)(R¹⁶))—) O, S, S(O), and S(O)₂, and provided that there are no —O—O— bonds, no —O—S— bonds, no O—S(O) bonds, no —O—S(O)₂bonds, and no —N—S— bonds in the ring, and provided that the ring does not comprise three adjacent nitrogen atoms,
  - (iii) at least one (e.g., 1 to 3, or 1 to 2, or 1) of A⁴, A⁵, and B¹to B⁴is a heteroatom, provided that when A⁴is a heteroatom said heteroatom is N, and when A⁵is a heteroatom said heteroatom is N, and when B¹is a heteroatom said heteroatom is N, and the heteroatoms for B²to B⁴(when one or more of B²to B⁴are heteroatoms) are selected from the group consisting of: N, O, S, S(O), and S(O)₂,
  - (iv) the total number of heteroatoms in said heterocycloalkyl Ring (B) is 1 to 4, and
  - (v) each substitutable A⁴, A⁵, and B¹to B⁴C is optionally substituted with 1 or 2 independently selected R^21Bgroups (and the substitution on each carbon is independent of the substitutions on the remaining carbons, and those skilled in the art will appreciate that the total number of optional substitutents on a carbon is determined by the number bonds in the ring to the ring atom), and
  - (vi) each substitutable B²to B⁴N is optionally substituted with one R^21Agroup and each R^21Afor each N is independently selected,
- (f) in said heterocycioalkenyl Ring (B):
  - (i) B¹is selected from the group consisting of N and C,
  - (ii) B², B³and B⁴are each independently selected from the group consisting of: N, C, —(C═O)— and —(C═NR^21A)— (e.g., —(C═N—OR¹⁵)—, and —(C═N—N(R¹⁵)(R¹⁶))—), O, S, S(O), and S(O)₂, and provided that there are no —O—O— bonds, no —O—S— bonds, no O—S(O) bonds, no —O—S(O)₂bonds, and no —N—S— bonds in the ring, and provided that the ring does not comprise three adjacent nitrogen atoms,
  - (iii) at least one (e.g., 1 to 3, or 1 to 2, or 1) of A⁴, A⁵, and B¹to B⁴is a heteroatom, provided that when A⁴is a heteroatom said heteroatom is N, and when A⁵is a heteroatom said heteroatom is N, and when B¹is a heteroatom said heteroatom is N, and the heteroatoms for B²to B⁴(when one or more of B²to B⁴are heteroatoms) are selected from the group consisting of: N, O, S, S(O), and S(O)₂,
  - (iv) the total number of heteroatoms in said heterocycloalkenyl Ring (B) is 1 to 4, and
  - (v) each substitutable A⁴, A⁵, and B¹to B⁴C is optionally substituted with 1 or 2 independently selected R^21Bgroups (and the substitution on each carbon is independent of the substitutions on the remaining carbons, and those skilled in the art will appreciate that the total number of optional substitutents on a carbon is determined by the number bonds in the ring to the ring atom),
  - (vi) each substitutable B²to B⁴N is optionally substituted with one R^21Agroup and each R^21Afor each N is independently selected, and
  - (vii) said heterocycloalkenyl Ring (B) comprises one or two double bonds (and in one example one double bond, and in another example two double bonds); and
- (g) in said heteroaryl Ring (B):
  - (i) B¹is C,
  - (ii) B²to B⁴are each independently selected from the group consisting of C and N,
  - (iii) at least one (e.g., 1 to 4, or 1 to 3, or 1 to 2, or 1) of A⁴, A⁵, and B²to B⁴is a heteroatom (e.g., at least one of A⁴or A⁵is N, or at least one of B²to B⁴is N), and
  - (iv) the total number of heteroatoms in said heteroaryl Ring (B) is 1 to 3 and wherein each substitutable B²to B⁴C is optionally substituted with one R^21Bgroup (and the substitution on each carbon is independent of the substitutions on the remaining carbons);

R³is selected from the group consisting of: aryl- (e.g., phenyl), heteroaryl- (e.g., pyridyl), cycloalkyl-, cycloalkenyl, cycloalkylalkyl-, heterocyclyl-, heterocyclenyl-, heterocyclylalkyl-, heterocyclyalkenyl-, fused benzocycloalkyl- (i.e., benzofusedcycloalkyl-), fused benzoheterocycbalkyl- (i.e., benzofusedheterocycloalkyl-), fused heteroarylcycloalkyl- (i.e., heteroarylfusedcycloalkyl-), fused heteroarylheterocycloalkyl- (i.e., heteroarylfusedheterocycloalkyl-), fused cycloalkylaryl (i.e., cycloalkyfusedlaryl-), fused heterocycloalkylaryl- (i.e., heterocycloalkylfusedaryl-), fused cycloalkylheteroaryl- (i.e., cycloalkylfusedheteroaryl-), fused heterocycloalkylheteroaryl- (i.e., heterocycloalkylfusedheteroaryl-),

wherein X is selected from the group consisting of: O, —N(R¹⁴)— and —S—; and wherein each of said R³moieties is optionally substituted with 1-5 independently selected R²¹groups;

R⁴is selected from the group consisting of: arylalkoxy-, heteroarylalkoxy-, arylalkylamino-, heteroarylalkylamino-, aryl, heteroaryl, cycloalkyl-, cycloalkenyl, heterocyclyl, heterocyclenyl, and heterocyclyalkyl-, wherein each of said R⁴arylalkoxy-, heteroarylalkoxy-, arylalkylamino-, heteroarylalkylamino-, aryl, heteroaryl, heterocyclyl, heterocyclenyl, and heterocyclyalkyl- is optionally substituted with 1-5 independently selected R²¹groups; or

R³and R⁴are linked together to form a fused tricyclic ring system wherein R³and R⁴are as defined above and the ring linking R³and R⁴is an alkyl ring, or a heteroalkyl ring, or an aryl ring, or a heteroaryl ring, or an alkenyl ring, or a heteroalkenyl ring (for example, the tricyclic ring system is formed by linking the atoms adjacent to the atoms by which R³and R⁴are bound together);

R⁵is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, —CN, —C(O)R¹⁵, —C(O)OR¹⁵, —C(O)N(R¹⁵)(R¹⁶), —S(O)N(R¹⁵)(R¹⁶), —S(O)₂N(R¹⁵)(R¹⁶), —C(═NOR¹⁵)R¹⁶, and —P(O)(OR¹⁵)(OR¹⁶); or

R⁵taken together with R¹and the nitrogen to which they are bound form a heterocycloalkyl or heterocycloalkenyl ring fused to said R¹ring, said fused ring is optionally substituted with 1 to 5 independently selected R²¹groups;

R⁶and R⁷are each independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, aryl, arylalkyl-, alkylaryl-, cycloalkyl, cycloalkylalkyl-, heteroaryl, heteroarylalkyl-, heterocyclyl (i.e., heterocycloalkyl) and heterocyclylalkyl- (i.e., heterocycloalkenyl), wherein independently each of said alkyl, alkenyl and alkynyl, aryl, arylalkyl-, alkylaryl-, cycloalkyl, cycloalkylalkyl-, heteroaryl, heteroarylalkyl-, heterocyclyl and heterocyclylalkyl- is optionally substituted with 1 to 5 independently selected R²¹groups; or

R⁶taken together with R¹and the carbon to which they are bound form a cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl ring fused to said R¹ring, said fused ring is optionally substituted with 1 to 5 independently selected R²¹groups; or

R⁶and R⁷taken together with the carbon to which they are bound form a spirocycloalkyl ring, a spirocycloalkenyl ring, a spiroheterocycloalkyl ring, or a spiroheterocyclalkenyl ring, and wherein the Spiro ring is optionally substituted with 1-5 independently selected R²¹groups;

R^15Aand R^16Aare independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, arylheterocyclyl, (R¹⁶)_q-alkyl, (R¹⁸)_q-cycloalkyl, (R¹⁸)_q-cycloalkylalkyl, (R¹⁸)_q-heterocyclyl, (R¹⁸)_q-heterocyclylalkyl, (R¹⁸)_q-aryl, (R¹⁸)_q-arylalkyl, (R¹⁸)_q-heteroaryl and (R¹⁸)_q-heteroarylalkyl, wherein q is 1 to 5 and each R¹⁸is independently selected (and those skilled in the art will appreciate that the R¹⁸moieties can be bound to any available substitutable atom);

R¹⁵, R¹⁶and R¹⁷are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, arylheterocyclyl, (R¹⁸)_q-alkyl, (R¹⁸)_q-cycloalkyl, (R¹⁸)_q-cycloalkylalkyl, (R¹⁸)_q-heterocyclyl, (R¹⁸)_q-heterocyclylalkyl, (R¹⁸)_q-aryl, (R¹⁸)_q-arylalkyl, (R¹⁸)_q-heteroaryl and (R¹⁸)_q-heteroarylalkyl, wherein q is 1 to 5 and each R¹⁸is independently selected (and those skilled in the art will appreciate that the R¹⁸moieties can be bound to any available substitutable atom);

each R¹⁸is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, —NO₂, halo, heteroaryl, HO-alkyoxyalkyl, —CF₃, —CN, alkyl-CN, —C(O)R¹⁸, —C(O)OH, —C(O)OR¹⁹, —C(O)NHR²⁰, —C(O)NH₂, —C(O)NH₂—C(O)N(alkyl)₂, —C(O)N(alkyl)(aryl), —C(O)N(alkyl)(heteroaryl), —SR¹⁹, —S(O)₂R²⁰, —S(O)NH₂, —S(O)NH(alkyl), —S(O)N(alkyl)(alkyl), —S(O)NH(aryl), —S(O)₂NH₂, —S(O)₂NHR¹⁹, —S(O)₂NH(heterocyclyl), —S(O)₂N(alkyl)₂, —S(O)₂N(alkyl)(aryl), —OCF₃, —OH, —OR²⁰, —O-heterocyclyl, —O-cycloalkylalkyl, —O-heterocyclylalkyl, —NH₂, —NHR²⁰, —N(alkyl)₂, —N(arylalkyl)₂, —N(arylalkyl)-(heteroarylalkyl), —NHC(O)R²⁰, —NHC(O)NH₂, —NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl), —N(alkyl)C(O)NH(alkyl), —N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O)₂R²⁰, —NHS(O)₂NH(alkyl), —NHS(O)₂N(alkyl)(alkyl), —N(alkyl)S(O)₂NH(alkyl) and —N(alkyl)S(O)₂N(alkyl)(alkyl); or

alternately, two R¹⁸moieties on adjacent carbons can be linked together to form:

R¹⁹is alkyl, cycloalkyl, aryl, arylalkyl or heteroarylalkyl;

R²⁰is alkyl, cycloalkyl, aryl, halo substituted aryl, arylalkyl, heteroaryl or heteroarylalkyl;

each R²¹group is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocyclyl (i.e., heterocycloalkyl), heterocyclylalkyl (i.e., heterocycloalkylalkyl), aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —CN, —OR¹⁵, —C(O)R¹⁵, —C(O)OR¹⁶, —C(O)N(R¹⁵)(R¹⁶), —P(O)(CH₃)₂, —SO(═NR¹⁵)R¹⁶—, —SF₅, —OSF₅, —Si(R^15A)₃wherein each R^15Ais independently selected, —SR¹⁵, —S(O)N(R¹⁵)(R¹⁶), —CH(R¹⁵)(R¹⁶), —S(O)₂N(R¹⁵)(R¹⁶), —C(═NOR¹⁵)R¹⁶, —P(O)(OR¹⁵)(OR¹⁶), —N(R¹⁵)(R¹⁶), -alkyl-N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —CH₂—R¹⁵, —CH₂N(R¹⁵)(R¹⁶), —N(R¹⁵)S(O)R^16A, —N(R¹⁵)S(O)₂R^16A, —CH₂—N(R¹⁵)S(O)₂R^16A, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷), —N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)OR¹⁶, —CH₂—N(R¹⁵)C(O)OR¹⁶, —S(O)R^15A, ═NOR¹⁵, —N₃, —NO₂, —S(O)₂R^15A, —O—N═C(R¹⁵)₂(wherein each R¹⁵is independently selected), and —O—N═O(R¹⁵)₂wherein said R¹⁵groups are taken together with the carbon atom to which they are bound to form a 5 to 10 membered ring and wherein said ring optionally contains 1 to 3 heteroatoms independently selected from the group consisting of —O—, —S—, —S(O)—, —S(O)₂—, and —NR^21A;

each R^21Ais independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocyclyl (i.e., heterocycloalkyl), heterocyclylalkyl (i.e., heterocycloalkylalkyl), aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —OR¹⁵, —CN, -alkyl-(R¹⁵)(R¹⁶), —CH(R¹⁵)(R¹⁶), —CH₂—N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —CH₂—R¹⁵; —CH₂N(R¹⁵)(R¹⁶), —C(O)R¹⁵, —C(O)OR¹⁵, —C(O)N(R¹⁵)(R¹⁶), —C(═NOR¹⁵)R¹⁶, —CH₂—N(R¹⁵)S(O)₂R^16A, —CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —CH₂—N(R¹⁵)C(O)OR¹⁶, —C(R¹⁵)═NOR¹⁶, —S(O)R^15A; —S(O)(OR¹⁵), —S(O)₂(OR¹⁵), —S(O)₂R^15A, —S(O)N(R¹⁵)(R¹⁶), —S(O)₂N(R¹⁵)(R¹⁶), —P(O)(OR¹⁵)(OR¹⁶), —N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶, —N(R¹⁵)S(O)R^16A, —N(R¹⁵)S(O)₂R^16A, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷), —N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)OR¹⁶, —N₃, —NO₂, —P(O)(CH₃)₂, —SO(═NR¹⁵)R¹⁶—, —SF₅, and —OSF₅;

each R^21Bgroup is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocyclyl (i.e., heterocycloalkyl), heterocyclylalkyl (i.e., heterocycloalkylalkyl), aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —OR¹⁵, —ON, -alkyl-(R¹⁵)(R¹⁶), —CH(R¹⁵)(R¹⁶), —CH₂—N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —CH₂—R¹⁵, —CH₂N(R¹⁵)(R¹⁶), —C(O)R¹⁵, —C(O)OR¹⁵, —C(O)N(R¹⁵)(R¹⁶), —C(═NOR¹⁵)R¹⁶, —CH₂—N(R¹⁵)S(O)₂R^16A, —CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —CH₂—N(R¹⁵)C(O)OR¹⁶, —C(R¹⁵)═NOR¹⁶, —SR¹⁵; —S(O)R^15A; —S(O)(OR¹⁵), —S(O)₂(OR¹⁵), —S(O)₂R^15A, —S(O)N(R¹⁵)(R¹⁶), —S(O)₂N(R¹⁵)(R¹⁶), —P(O)OR¹⁵)(OR¹⁶), —N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶, —N(R¹⁵)S(O)R^16A, —N(R¹⁵)S(O)₂R^16A, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷), —N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R)C(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)OR¹⁶, —N₃, —NO₂, —P(O)(CH₃)₂, —SO(═NR¹⁵)R¹⁶—, —SF₅, —OSF₅, and —Si(R^15A)₃wherein each R^15Ais independently selected;

Independently, each alkyl, cycloalkenyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl R²¹, R^21A, and R^21Bgroup is optionally substituted by 1 to 5 independently selected R²²groups wherein each R²²group is independently selected from the group consisting of alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, halo, —CF₃, —CN, —OR¹³, —C(O)R¹⁵, —C(O)OR¹⁵, -alkyl-C(O)OR¹⁵, C(O)N(R¹⁵)(R¹⁶), —S(O)N(R¹⁵)(R¹⁶), —S(O)₂N(R¹⁵)(R¹⁶), —C(═NOR¹⁵)R¹⁶, —P(O)(OR¹⁵)(OR¹⁶), —N(R¹⁵)(R¹⁶), -alkyl-N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)R¹⁶, —N(R¹⁵)S(O)R¹⁶, —N(R¹⁵)S(O)₂R¹⁶, —CH₂—N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷), —N(R¹⁵)S(O)N(R¹⁸)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —CH₂—N(R¹³)C(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)OR¹⁶, —CH₂—N(R¹⁵)C(O)OR¹⁶, —N₃, ═NOR¹⁵, —NO₂, —S(O)R^15Aand —S(O)₂R^15A; and With the proviso that when R³is aryl and R¹comprises a 5 or 6-membered aryl or heteroaryl ring, then said 5 or 6-membered aryl or heteroaryl ring is not substituted with an R²¹group that is selected from the group consisting of the moieties: —O-(5 or 6 membered aryl), —S-(5 or 6 membered aryl), —S(O)₂-(5 or 6 membered aryl), —N(R¹⁵)-(5 or 6 membered aryl), —C(O)-(5 or 6 membered aryl), -alkyl-(5 or 6 membered aryl), —O-(5 or 6 membered heteroaryl), —S-(5 or 6 membered heteroaryl), —S(O)₂-(5 or 6 membered heteroaryl), —N(R¹⁵)-(5 or 6 membered heteroaryl), —C(O)-(5 or 6 membered heteroaryl), and -alkyl-(5 or 6 membered heteroaryl).

Those skilled in the art will appreciate that the above proviso means that when R³is aryl and R¹comprises a 5 or 6-membered aryl or heteroaryl ring, then said 5 or 6-membered aryl or heteroaryl ring is not substituted with —O-(5 or 6 membered aryl), —S-(5 or 6 membered aryl), —S(O)₂-(5 or 6 membered aryl), —N(R¹⁵)-(5 or 6 membered aryl), —C(O)-(5 or 6 membered aryl), -alkyl-(5 or 6 membered aryl), —O-(5 or 6 membered heteroaryl), —S-(5 or 6 membered heteroaryl), —S(O)₂-(5 or 6 membered heteroaryl), —N(R¹⁵)-(5 or 6 membered heteroaryl), —C(O)-(5 or 6 membered heteroaryl), or -alkyl-(5 or 6 membered heteroaryl).

The compounds of this invention are useful for treating central nervous system disorders such as, for example, neurodegenerative diseases such as Alzheimer's disease and other diseases relating to the deposition of amyloid protein. They are especially useful for reducing Amyloid beta (hereinafter referred to as Aβ) production which is effective in the treatment of diseases caused by Aβ such as, for example, Alzheimers and Down Syndrome.

Thus, for example, the compounds of this invention can be used to treat the following diseases or conditions: Alzheimers disease, mild cognitive impairment (MC1), Downs Syndrome, Glaucoma (Guo et. al., Proc. Natl. Acad. Sci. USA 104, 13444-13449 (2007)), Cerebral amyloid angiopathy, stroke or dementia (Frangione et al., Amyloid: J. Protein folding Disord. 8, suppl. 1, 36-42 (2001), Microgliosis and brain inflammation (M P Lamber, Proc. Natl. Acad. Sci. USA 95, 6448-53 (1998)), and Olfactory function loss (Getchell, et. al. Neurobiology of Aging, 663-673, 24, 2003).

In one embodiment of this invention R¹is selected from the group consisting of: alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl (e.g., heterocycloalkyl), cycloalkenyl, aryl (e.g., phenyl), heteroaryl (e.g., pyridyl), heterocyclenyl (i.e., heterocycloalkenyl), wherein each of said: alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkenyl, aryl, heteroaryl, and heterocyclenyl R¹groups is optionally substituted with 1-5 independently selected R²¹groups.

In another embodiment of this invention Ring (A) is heteroaryl wherein:

- (a) A¹, A⁴, and A⁵are each independently selected from the group consisting of C and N,
- (b) A²and A³are each independently selected from the group consisting of: N, S, O or C, and wherein each substitutable C is optionally substituted with one R^21Bgroup and each R^21Bfor each C is independently selected, and wherein each substitutable N is optionally substituted with one R^21Agroup and each R^21Afor each N is independently selected,
- (c) provided that at least one (e.g., 1 to 3, or 1 to 2, or 1) of A¹to A⁵is a heteroatom (i.e., at least one of A¹to A⁵is selected from the group consisting of N, S and O), and provided that the total number of heteroatoms in Ring (A) is 1 to 3, and
- (d) provided that Ring (A) does not contain two adjacent ring O atoms, and does not contain adjacent O and S atoms (i.e., there are no —O—O—, and no —O—S—, and no —S—O— ring members in Ring (A)).

In another embodiment of this invention R³is selected from the group consisting of: phenyl and pyridyl, wherein said R³group is optionally substituted with 1 to 4 independently selected R²¹groups.

In another embodiment of this invention R⁴is a five membered heteroaryl ring optionally substituted with 1 to 4 independently selected R²¹groups.

In one embodiement of this invention:

- R¹is selected from the group consisting of: alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl (e.g., heterocycloalkyl), cycloalkenyl, aryl (e.g., phenyl), heteroaryl (e.g., pyridyl), heterocyclenyl (i.e., heterocycloalkenyl), wherein each of said: alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkenyl, aryl, heteroaryl, and heterocyclenyl R¹groups is optionally substituted with 1-5 independently selected R²¹groups;
- Ring (A) is heteroaryl wherein:
  - (a) A¹, A⁴, and A⁵are each independently selected from the group consisting of C and N,
  - (b) A²and A³are each independently selected from the group consisting of: N, S, O or C, and wherein each substitutable C is optionally substituted with one R^21Bgroup and each R^21Bfor each C is independently selected, and wherein each substitutable N is optionally substituted with one R^21Agroup and each R^21Afor each N is independently selected,
  - (c) provided that at least one (e.g., 1 to 3, or 1 to 2, or 1) of A¹to A⁵is a heteroatom (i.e., at least one of A¹to A⁵is selected from the group consisting of N, S and O), and provided that the total number of heteroatoms in Ring (A) is 1 to 3, and
  - (d) provided that Ring (A) does not contain two adjacent ring O atoms, and does not contain adjacent O and S atoms (i.e there are no —O—O—, and no —O—S—, and no —S—O— ring members in Ring (A));
- R³is selected from the group consisting of: phenyl and pyridyl, wherein said R³group is optionally substituted with 1 to 4 independently selected R²¹groups; and
- R⁴is a five membered heteroaryl ring optionally substituted with 1 to 4 independently selected R²¹groups.

Examples of moieties formed when R³and R⁴are linked together to form a fused tricyclic ring system include, but are not limited to:

wherein R³and R⁴are as defined for formula (I), and Ring C is the ring linking R³and R⁴, that is Ring C is an alkyl ring, or a heteroalkyl ring, or an aryl ring, or a heteroaryl ring, or an alkenyl ring, or a heteroalkenyl ring.

Examples of moieties formed when R³and R⁴are linked together to form a fused tricyclic ring system include, but are not limited to:

wherein R³and R⁴are as defined for formula (I), and Ring C is the ring linking R³and R⁴, that is Ring C is a heteroalkyl ring, or a heteroaryl ring, or a heteroalkenyl ring.

In one example, the fused tricyclic ring system formed when R³and R⁴are linked together is

wherein Ring C is a heteroalkyl ring, or a heteroaryl ring, or a heteroalkenyl ring, thus, for example, the tricyclic ring system is formed by linking the atoms adjacent to the atoms by which R³and R⁴are bound together), and wherein said fused tricyclic ring system is optionally substituted with 1 to 5 independently selected R²¹groups.

Other examples of moieties formed when R³and R⁴are linked together to form a fused tricyclic ring system include, but are not limited to:

In one embodiment of this invention R³is bound to A¹and L is bound to B¹. Thus, in this embodiment the compound of formula (I) is a compound of the formula:

In another embodiment of this invention R³is bound to B¹and L is bound to A¹. Thus, in this embodiment the compound of formula (I) is a compound of the formula:

In another embodiment of this invention the R⁴—R³— moiety is:

Thus, in another embodiment of this invention the compound of formula (I) is a compound of the formula:

In another embodiment of this invention the compound of formula a compound of the formula:

In another embodiment of this invention the compound of formula (I) is a compound of the formula:

In another embodiment of this invention the compound of formula (I) is a compound the formula:

Another embodiment of this is directed to compounds of formula (I) wherein at least one (e.g., 1 to 3, or 1-2, or 1) group selected from the group consisting of: —SF₅, —OSF₅, and —Si(R^15A)₃is present, and wherein each R^15Ais independently selected, and wherein when there is more than one group, each group is independently selected.

Another embodiment of this is directed to compounds of formula (I) wherein at least one (e.g., 1 to 3, or 1-2, or 1) group selected from the group consisting of: —SF₅and —OSF₅is present, and wherein when there is more than one group, each group is independently selected.

In one embodiment of this invention one group selected from the group consisting of: —SF₅, —OSF₅, and —Si(R^15A)₃(wherein each R^15Ais independently selected) is present in the compounds of formula (I).

In another embodiment of this invention two groups selected from the group consisting of: —SF₅, —OSF₅, and —Si(R^15A)₃(wherein each R^15Ais independently selected) are present in the compounds of formula (I).

In another embodiment of this invention three groups selected from the group consisting of: —SF₅, —OSF₅, and —Si(R^15A)₃(wherein each R^15Ais independently selected) are present in the compounds of formula (I).

In another embodiment of this invention one group selected from the group consisting of: —SF₅, —OSF₅, and —Si(R^15A)₃(wherein each R^15Ais independently selected from the group consisting of alkyl (e.g., methyl and ethyl) and aryl (e.g., phenyl)) is present in the compounds of formula (I).

In another embodiment of this invention two groups selected from the group consisting of: —SF₅, —OSF₅, and —Si(R^15A)₃(wherein each R^15Ais independently selected from the group consisting of alkyl (e.g., methyl and ethyl) and aryl (e.g., phenyl)) are present in the compounds of formula (I).

In another embodiment of this invention three groups selected from the group consisting of: —SF₅, —OSF₅, and —Si(R^15A)₃(wherein each R^15Ais independently selected from the group consisting of alkyl (e.g., methyl and ethyl) and aryl (e.g., phenyl)) are present in the compounds of formula (I).

In another embodiment of this invention one group selected from the group consisting of: —SF₅, —OSF₅, and —Si(R^15A)₃(wherein each R^15Ais independently selected from the group consisting of methyl, ethyl and phenyl) is present in the compounds of formula (I).

In another embodiment of this invention two groups selected from the group consisting of: —SF₅, —OSF₅, and —Si(R^15A)₃(wherein each R^15Ais independently selected from the group consisting of methyl, ethyl and phenyl) are present in the compounds of formula (I).

In another embodiment of this invention three groups selected from the group consisting of: —SF₅, —OSF₅, and —Si(R^15A)₃(wherein each R^15Ais independently selected from the group consisting of methyl, ethyl and phenyl) are present in the compounds of formula (I).

In another embodiment of this invention two groups selected from the group consisting of: —SF₅, —OSF₅, and —Si(R^15A)₃(wherein each R^15Ais independently selected from the group consisting of methyl, ethyl and phenyl) are present in the compounds of formula (I), wherein at least one group is other than —Si(R^15A)₃.

In another embodiment of this invention three groups selected from the group consisting of: —SF₅, —OSF₅, and —Si(R^15A)₃(wherein each R^15Ais independently selected from the group consisting of methyl, ethyl and phenyl) are present in the compounds of formula (I), wherein at least one group is other than —Si(R^15A)₃.

In another embodiment of this invention one group selected from the group consisting of: —SF₅, —OSF₅, and —Si(R^15A)₃(wherein each R^15Ais independently selected from the group consisting of methyl and ethyl) is present in the compounds of formula (I).

In another embodiment of this invention two groups selected from the group consisting of: —SF₅, —OSF₅, and —Si(R^15A)₃(wherein each R^15Ais independently selected from the group consisting of methyl and ethyl) are present in the compounds of formula (I).

In another embodiment of this invention three groups selected from the group consisting of: —SF₅, —OSF₅, and —Si(R^15A)₃(wherein each R^15Ais independently selected from the group consisting of methyl and ethyl) are present in the compounds of formula (I).

In another embodiment of this invention two groups selected from the group consisting of: —SF₅, —OSF₅, and —Si(R^15A)₃(wherein each R^15Ais independently selected from the group consisting of methyl and ethyl) are present in the compounds of formula (I), wherein at least one group is other than —Si(R^15A)₃.

In another embodiment of this invention three groups selected from the group consisting of: —SF₅, —OSF₅, and —Si(R^15A)₃(wherein each R^15Ais independently selected from the group consisting of methyl and ethyl) are present in the compounds of formula (I), wherein at least one group is other than —Si(R^15A)₃.

In another embodiment of this invention one group selected from the group consisting of: —SF₅, —OSF₅, and —Si(R^15A)₃is present in the compounds of formula (I), and said —Si(R^15A)₃group is selected from the group consisting of: —Si(CH₃)₃, —Si(CH₃)₂phenyl, and —Si(CH₂CH₃)₂CH₈.

In another embodiment of this invention two groups selected from the group consisting of: —SF₅, —OSF₅, and —Si(R^15A)₃are present in the compounds of formula (I) and said —Si(R^15A)₃group is selected from the group consisting of: —Si(CH₃)₃, —Si(CH₃)₂phenyl, and —Si(CH₂CH₃)₂CH₃.

In another embodiment of this invention three groups selected from the group consisting of: —SF₅, —OSF₅, and —Si(R^15A)₃are present in the compounds of formula (I), and said —Si(R^15A)₃group is selected from the group consisting of: —Si(CH₃)₃, —Si(CH₃)₂phenyl, and —Si(CH₂CH₃)₂CH₃.

In another embodiment of this invention two groups selected from the group consisting of: —SF₅, —OSF₅, and —Si(R^15A)₃are present in the compounds of formula (I), wherein at least one group is other than —Si(R^15A)₃, and said —Si(R^15A)₃group is selected from the group consisting of: —Si(CH₃)₃, —Si(CH₃)₂phenyl, and —Si(CH₂CH₃)₂CH₃.

In another embodiment of this invention three groups selected from the group consisting of: —SF₅, —OSF₅, and —Si(R^15A)₃are present in the compounds of formula (I), wherein at least one group is other than —Si(R^15A)₃, and said —Si(R^15A)₃group is selected from the group consisting of: —Si(CH₃)₃, —Si(CH₃)₂phenyl, and —Si(CH₂CH₃)₂CH₃.

In another embodiment of this invention two groups selected from the group consisting of: —SF₅, —OSF₅, and —Si(R^15A)₃are present in the compounds of formula (I), and said —Si(R^15A)₃group is selected from the group consisting of: —Si(CH₃)₃and —Si(CH₂CH₅)₂CH₃.

In another embodiment of this invention one group selected from the group consisting of: —SF₅, —OSF₅, and —Si(CH₃)₃is present.

In another embodiment of this invention two groups selected from the group consisting of: —SF₅, —OSF₅, and —Si(CH₃)₃are present in the compounds of formula (I).

In another embodiment of this invention three groups selected from the group consisting of: —SF₅, —OSF₅, and —Si(CH₃)₃are present in the compounds of formula (I).

In another embodiment of this invention two groups selected from the group consisting of: —SF₅, —OSF₅, and —Si(CH₃)₃are present in the compounds of formula (I), wherein at least one group is other than —Si(CH₃)₃.

In another embodiment of this invention three groups selected from the group consisting of: —SF₅, —OSF₅, and —Si(R²⁴)₃are present in the compounds of formula (I), wherein at least one group is other than —Si(CH₃)₃.

In another embodiment of this invention one group selected from the group consisting of: —SF₅and —OSF₅is present in the compounds of formula (I).

In another embodiment of this invention two groups selected from the group consisting of: —SF₅and —OSF₅are present in the compounds of formula (I).

In another embodiment of this invention three groups selected from the group consisting of: —SF₅and —OSF₅are present in the compounds of formula (I).

In another embodiment of this invention one —SF₅group is present in the compounds of formula (I).

In another embodiment of this invention two —SF₅groups are present in the compounds of formula (I).

In another embodiment of this invention three —SF₅groups are present in the compounds of formula (I).

In another embodiment of this invention one —OSF₅group is present in the compounds of formula (I).

In another embodiment of this invention two —OSF₅groups are present in the compounds of formula (I).

In another embodiment of this invention three —OSF₅groups are present in the compounds of formula (I).

In another embodiment of this invention one —Si(R^15A)₃(wherein each R^15Ais independently selected) group is present in the compounds of formula (I).

In another embodiment of this invention two —Si(R^15A)₃(wherein each R^15Ais independently selected) groups are present in the compounds of formula (I).

In another embodiment of this invention three —Si(R^15A)₃(wherein each R^15Ais independently selected) groups are present in the compounds of formula (I).

In another embodiment of this invention one —Si(R^15A)₃(wherein each R^15Ais independently selected from the group consisting of alkyl (e.g., methyl and ethyl) and aryl (e.g., phenyl)) is present in the compounds of formula (I).

In another embodiment of this invention two —Si(R^15A)₃(wherein each R^15Ais independently selected from the group consisting of alkyl (e.g., methyl and ethyl) and aryl (e.g., phenyl)) is present in the compounds of formula (I).

In another embodiment of this invention three —Si(R^15A)₃(wherein each R^15Ais independently selected from the group consisting of alkyl (e.g., methyl and ethyl) and aryl (e.g., phenyl)) is present in the compounds of formula (I).

In another embodiment of this invention one —Si(R^15A)₃(wherein each R^15Ais independently selected from the group consisting of methyl, ethyl and phenyl) is present in the compounds of formula (I).

In another embodiment of this invention two —Si(R^15A)₃(wherein each R^15Ais independently selected from the group consisting of methyl, ethyl and phenyl) is present in the compounds of formula (I).

In another embodiment of this invention three —Si(R^15A)₃(wherein each R^15Ais independently selected from the group consisting of methyl, ethyl and phenyl) is present in the compounds of formula (I).

In another embodiment of this invention one —Si(R^15A)₃(wherein each R^15Ais independently selected from the group consisting of methyl and ethyl) is present in the compounds of formula (I).

In another embodiment of this invention two —Si(R^15A)₃(wherein each R^15Ais independently selected from the group consisting of methyl and ethyl) is present in the compounds of formula (I).

In another embodiment of this invention three —Si(R^15A)₃(wherein each R^15Ais independently selected from the group consisting of methyl and ethyl) is present in the compounds of formula (I).

In another embodiment of this invention one —Si(R^15A)₃group is present in the compounds of formula (I), and said —Si(R^15A)₃group is selected from the group consisting of: —Si(CH₃)₃, —Si(CH₃)₂phenyl, and —Si(CH₂CH₃)₂CH₃

In another embodiment of this invention two —Si(R^15A)₃groups are present in the compounds of formula (I), and said —Si(R^15A)₃groups are independently selected from the group consisting of: —Si(CH₃)₃, —Si(CH₃)₂phenyl, and —Si(CH₂CH₃)₂CH₃.

In another embodiment of this invention three —Si(R^15A)₃groups are present in the compounds of formula (I), and said —Si(R^15A)₃groups are independently selected from the group consisting of: —Si(CH₃)₃, —Si(CH₃)₂phenyl, and —Si(CH₂CH₃)₂CH₃.

In another embodiment of this invention one —Si(R^15A)₃group is present in the compounds of formula (I), and said —Si(R^15A)₃group is —Si(CH₃)₃.

In another embodiment of this invention two —Si(R^15A)₃groups are present in the compounds of formula (I), and said —Si(R^15A)₃groups are —Si(CH₃)₃.

In another embodiment of this invention three —Si(R^15A)₃groups are presen the compounds of formula (I), and said —Si(R^15A)₃groups are —Si(CH₃)₃.

In another embodiment of this invention one group selected from the group consisting of: —SF₅, —OSF₅, —Si(CH₃)₃, —Si(CH₃)₂phenyl, and —Si(CH₂CH₃)₂CH₃) is present in the compounds of formula (I).

In another embodiment of this invention one group selected from the group consisting of: —SF₅, —OSF₅, —Si(CH₃)₃, and —Si(CH₂CH₃)₂CH₃) is present in the compounds of formula (I).

In another embodiment of this invention one group selected from the group consisting of: —SF₅, —OSF₅, and —Si(CH₃)₃, is present in the compounds of formula (I).

In another embodiment of this invention one —SF₅group is present in the compounds of formula (I), and one or two additional groups selected from the group consisting of: —SF₅, —OSF₅, and —Si(R^15A)₃(wherein each R^15Ais independently selected) are also present in the compounds of formula (I).

In another embodiment of this invention one —SF₅group is present in the compounds of formula (I), and one or two additional groups selected from the group consisting of: —OSF₅, and —Si(R^15A)₃(wherein each R^15Ais independently selected) are also present in the compounds of formula (I).

In another embodiment of this invention one —OSF₅group is present in the compounds of formula (I), and one or two additional groups selected from the group consisting of: —SF₅, —OSF₅, and —Si(R^15A)₃(wherein each R^15Ais independently selected) are also present in the compounds of formula (I).

In another embodiment of this invention one —OSF₅group is present in the compounds of formula (I), and one or two additional groups selected from the group consisting of: —SF₅and —Si(R^15A)₃(wherein each R^15Ais independently selected) are also present in the compounds of formula (I).

In another embodiment of this invention one —SF₅group is present in the compounds of formula (I), and one or two additional groups selected from the group consisting of: —SF₅and —OSF₅are also present in the compounds of formula (I).

In another embodiment of this invention one —Si(R^15A)₃(wherein each R^15Ais independently selected) group is present in the compounds of formula (I), and one or two groups selected from the group consisting of: —SF₅, —OSF₅, and —Si(R^15A(wherein each R^15Ais independently selected) are also present in the compounds of formula (I).

In another embodiment of this invention one —Si(R^15A)₃(wherein each R^15Ais independently selected) group is present in the compounds of formula (I), and one or two groups selected from the group consisting of: —SF₅and —OSF₅are also present in the compounds of formula (I).

In another embodiment of this invention at least one group selected from the group consisting of: —SF₅, —OSF₅, and —Si(R^15A)₃(wherein each R^15Ais independently selected from the group consisting of alkyl (e.g., methyl and ethyl) and aryl (e.g., phenyl)) is present in the compounds of formula (I).

In another embodiment of this invention at least one group selected from the group consisting of: —SF₅, —OSF₅, and —Si(R^15A)₃(wherein each R^15Ais independently selected from the group consisting of alkyl (e.g., methyl and ethyl) and phenyl) is present in the compounds of formula (I).

In another embodiment of this invention at least one group selected from the group consisting of: —SF₅, —OSF₅, and —Si(R^15A)₃(wherein each R^15Ais independently selected from the group consisting of methyl, ethyl and phenyl) is present in the compounds of formula (I).

In another embodiment of this invention at least one group selected from the group consisting of: —SF₅, —OSF₅, —Si(CH₃)₃, —Si(CH₃)₂phenyl, and —Si(CH₂CH₃)₂CH₃) is present in the compounds of formula (I).

In another embodiment of this invention at least one group selected from the group consisting of: —SF₅, —OSF₅, and —Si(CH₃)₃is present in the compounds of formula (I).

In another embodiment of this invention one group selected from the group consisting of: —SF₅, —OSF₅, and —Si(R^15A)₃(wherein each R^15Ais independently selected) is present in the compounds of formula (I).

In another embodiment of this invention one group selected from the group consisting of: —SF₅, —OSF₅, and —Si(R^15A)₃(wherein each R^15Ais independently selected from the group consisting of alkyl (e.g., methyl and ethyl) and phenyl) is present in the compounds of formula (I).

In another embodiment of this invention one group selected from the group consisting of: —SF₅, —OSF₅, and —Si(R^15A)₃(wherein each R^15Ais independently selected from the group consisting of methyl ethyl and phenyl) is present in the compounds of formula (I).

In another embodiment of this invention one group selected from the group consisting of: —SF₅, —OSF₅, and —Si(CH₃)₃, is present in the compounds of formula (I).

In another embodiment of this invention two groups independently selected from the group consisting of: —SF₅, —OSF₅, and —Si(R^15A)₃(wherein each R^15Ais independently selected from the group consisting of alkyl (e.g., methyl and ethyl) and aryl (e.g., phenyl)) are present in the compounds of formula (I).

In another embodiment of this invention two groups independently selected from the group consisting of: —SF₅, —OSF₅, and —Si(R^15A)₃(wherein each R^15Ais independently selected from the group consisting of alkyl (e.g., methyl and ethyl) and phenyl) are present in the compounds of formula (I).

In another embodiment of this invention two groups selected from the group consisting of: —SF₅, —OSF₅, and —Si(R^15A)₃(wherein each R^15Ais independently selected from the group consisting of methyl, ethyl and phenyl) are present in the compounds of formula (I).

In another embodiment of this invention two groups independently selected from the group consisting of: —SF₅, —OSF₅, —Si(CH₃)₃, —Si(CH₃)₂phenyl, and —Si(CH₂CH₃)₂CH₃) is present in the compounds of formula (I).

In another embodiment of this invention two groups independently selected from the group consisting of: —SF₅, —OSF₅, —Si(CH₃)₃, and —Si(CH₂CH₃)₂CH₃) are present in the compounds of formula (I).

In another embodiment of this invention two groups independently selected from the group consisting of: —SF₅, —OSF₅, and —Si(CH₃)₃are present in the compounds of formula (I).

In another embodiment of this invention three groups independently selected from the group consisting of: —SF₅, —OSF₅, and —Si(R^15A)₃(wherein each R^15Ais independently selected from the group consisting of alkyl (e.g., methyl and ethyl) and aryl (e.g., phenyl)) are present in the compounds of formula (I).

In another embodiment of this invention three groups independently selected from the group consisting of: —SF₅, —OSF₅, and —Si(R^15A)₃(wherein each R^15Ais independently selected from the group consisting of alkyl (e.g., methyl and ethyl) and phenyl) are present in the compounds of formula (I).

In another embodiment of this invention three groups selected from the group consisting of: —SF₅, —OSF₅, and —Si(R^15A)₃(wherein each R^15Ais independently selected from the group consisting of methyl, ethyl and phenyl) are present in the compounds of formula (I).

In another embodiment of this invention three groups independently selected from the group consisting of: —SF₅, —OSF₅, —Si(CH₃)₃, —Si(CH₃)₂phenyl, and —Si(CH₂CH₃)₂CH₃) is present in the compounds of formula (I).

In another embodiment of this invention three groups independently selected from the group consisting of: —SF₅, —OSF₅, —Si(CH₃)₃, and —Si(CH₂CH₃)₂CH₃) are present in the compounds of formula (I).

In another embodiment of this invention three groups independently selected from the group consisting of: —SF₅, —OSF₅, and —Si(CH₃)₃are present in the compounds of formula (I).

In another embodiment of this invention at least one group selected from the group consisting of: —SF₅, —OSF₅, and —Si(R^15A)₃(wherein each R^15Ais the same or different alkyl group) is present in the compounds of formula (I).

In another embodiment of this invention at least one group selected from the group consisting of: —SF₅, —OSF₅, and —Si(R^15A)₃(wherein each R^15Ais independently selected from the group consisting of methyl and ethyl) is present in the compounds of formula (I).

In another embodiment of this invention one —SF₅group is present in the compounds of formula (I), and one or two groups selected from the group consisting of: —SF₅and —OSF₅are also present in the compounds of formula (I).

In another embodiment of this invention one —OSF₅group is present in the compounds of formula (I), and one or two groups selected from the group consisting of: —SF₅and —OSF₅are also present in the compounds of formula (I).

In another embodiment of this invention L is —C(R⁶)(R⁷)—.

In another embodiment of this invention L is —C(R⁶)(R⁷)— wherein R⁶and R⁷are taken together with the carbon atom to which they are bound to form a spirocycloalkyl ring (e.g., cyclopropyl).

In another embodiment of this invention L is —C(R⁶)(R⁷)— wherein R⁶and R⁷are taken together with the carbon atom to which they are bound to form a spirocycloalkenyl ring.

In another embodiment of this invention L is —C(R⁶)(R⁷)— wherein R⁶and R⁷are taken together with the carbon atom to which they are bound to form a spiroheterocycloalkyl ring.

In another embodiment of this invention L is —C(R⁶)(R⁷)— wherein R⁶and R⁷are taken together with the carbon atom to which they are bound to form a spiroheterocycloalkenyl ring.

In another embodiment of this invention L is —C(R⁶)(R⁷)— wherein R⁶and R⁷are independently selected from the group consisting of: H, alkyl, and alkyl substituted with one R²¹group.

In another embodiment of this invention L is —C(R⁶)(R⁷)— wherein R⁶and R⁷are independently selected from the group consisting of: H, methyl, and methyl substituted with one R²¹group.

In another embodiment of this invention L is —C(R⁶)(R⁷)— wherein R⁶and R⁷are independently selected from the group consisting of: H, alkyl, and alkyl substituted with one R²¹group wherein said R²¹group is —OR¹⁵.

In another embodiment of this invention L is selected from the group consisting of:

In another embodiment of this invention L is —CH₂—.

In another embodiment of this invention L is —CH(CH₃)—.

In another embodiment of this invention L is —CH(CH₂OH)—.

In another embodiment of this invention R¹is phenyl.

In another embodiment of this invention R¹is phenyl substituted with 1 to 3 halo atoms.

In another embodiment of this invention R¹is phenyl substituted with 1 to 3 F atoms.

In another embodiment of this invention R¹is selected from the group consisting of:

In another embodiment of this invention R¹is phenyl.

In another embodiment of this invention R¹is:

In another embodiment of his invention R¹is:

In another embodiment of this invention R¹is:

In another embodiment of this invention R¹is

In another embodiment of this invention R¹is:

In another embodiment, R¹is phenyl substituted with 1-3 halos independently selected from the group consisting of F and Cl. In one example said phenyl is substituted with one F and one Cl.

In another embodiment R¹is aryl (e.g., phenyl) substituted with 1 to 3 independently selected R²¹moieties wherein at least one R²¹moiety is selected from the group consisting of —SF₅, —OSF₅and —Si(R^15A)₃(and in one example each R^15Ais the same or different alkyl, and in another example the —Si(R²⁴)₃group is —Si(CH₃)₃or —Si(CH₂CH₃)₂CH₃, and in another example the —Si(R²⁴)₃group is —Si(C_1-13)₃)₃.

In another embodiment R¹is aryl (e.g., phenyl) substituted with 1 to 3 R²¹moieties independently selected from the group consisting of: halo (e.g., F), —SF₅, —OSF₅and —Si(R^15A)₃(and in one example each R^15Ais the same or different alkyl, and in another example the —Si(R^15A)₃group is —Si(CH₃)₃or —Si(CH₂CH₃)₂CH₃, and in another example the —Si(R^15A)₃group is —Si(CH₃)₃), and wherein at least one R²¹moiety is selected from the group consisting of —SF₅, —OSF₅and —Si(R^15A)₃(and in one example each R^15Ais the same or different alkyl, and in another example the —Si(R^15A)₃group is —Si(CH₃)₃or —Si(CH₂CH₃)₂CH₃, and in another example the —Si(R²⁴)₃group is —Si(CH₃)₃).

In another embodiment R¹is aryl (e.g., phenyl) substituted with 1 to 3 R²¹moieties independently selected from the group consisting of: halo (e.g., F), —SF₅and —OSF₅, and wherein at least one R²¹moiety is selected from the group consisting of —SF₅and —OSF₅.

In another embodiment R¹is aryl (e.g., phenyl) substituted with 1 to 3 independently selected R²¹moieties wherein at least one R²¹moiety is selected from the group consisting of —SF₅, —OSF₅and —Si(R^15A)₃(and in one example each R^15Ais the same or different alkyl, and in another example the —Si(R^15A)₃group is —Si(CH₃)₃or —Si(CH₂CH₃)₂CH₃, and in another example the —Si(R^15A)₃group is —Si(CH₃)₃).

In another embodiment, R¹is phenyl substituted with 1-3 R²¹groups independently selected from the group consisting of halos, —SF₅and —OSF₅, wherein at least one R²¹group is —SF₅or —OSF₅.

In another embodiment, R¹is phenyl substituted with 1-3 R²¹groups independently selected from the group consisting of F, Cl, —SF, and —OSF₅.

In another embodiment, R¹is phenyl substituted with 1-3 R²¹groups independently selected from the group consisting of —SF₅and —OSF₅.

In another embodiment, R¹is phenyl substituted with 1-3 R²¹groups independently selected from the group consisting of F, —SF₅and —OSF₅, wherein at least one R²¹group is —SF₅or —OSF₅.

In another embodiment, R¹is phenyl substituted with one —SF₅group.

In another embodiment. R¹is phenyl substituted with two —SF₅groups.

In another embodiment, R¹is phenyl substituted with three —SF₅groups.

In another embodiment, R¹is phenyl substituted with one —OSF₅group.

In another embodiment, R¹is phenyl substituted with two —OSF₅groups.

In another embodiment, R¹is phenyl substituted with three —OSF₅groups.

In another embodiment, R¹is phenyl substituted with 1 F.

In another embodiment, R¹is phenyl substituted with 1 F, and also substituted with 1 to 2 groups independently selected from the group consisting of —SF₅and —OSF₅.

In another embodiment R¹is phenyl substituted with 2 F,

In another embodiment R¹is phenyl substituted with 3F.

In another embodiment of this invention L is selected from the group consisting of: